Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs).

INTRODUCTION: Cotrimoxazole (Sulfamethoxazole-Trimethoprim, SXT) has interesting characteristics for the treatment of bone and joint infection (BJI): a broad spectrum of activity with adequate bone diffusion and oral and intravenous formulations. However, its efficacy and safety in BJIs are poorly documented and its use remains limited.
METHODS: We conducted a retrospective study in 2 reference centers for BJIs from 2013 to 2018 among patients treated with SXT for a BJI. Data were collected from patient's medical charts. Outcomes and adverse events were evaluated at day (D)7, D45 and D90.
RESULTS: We analyzed 51 patients with a mean age of 60 ± 20 (SD) years of which 76% presented with an orthopedic device infection (ODI). Gram-negative bacilli (GNB) were involved in 47% of BJIs (n = 24). Moreover, they were often polymicrobial infections (41%). Doses of SXT ranged from 800/160mg bid (61%; n = 31) to 800/160mg tid (39%; n = 20). Median SXT treatment duration was 45 days (IQR 40-45). SXT was part of a dual therapy in 84% of patients (n = 43), associated mainly with fluoroquinolones (n = 17) or rifampicin (n = 14). Outcome was favorable at D7 in 98% (n = 50), at D45 in 88.2% (n = 45) and at D90 in 78.4% (n = 40). The second agent combined with SXT was not an independent factor of favorable outcome (p = 0.97). Adverse events were reported in 8% (n = 4) of patients, with a median of 21 days (IQR 20-30) from SXT initiation and led to discontinuation (n = 3).
CONCLUSION: SXT appears to be effective for treatment of BJIs as a salvage therapy, even in GNB or polymicrobial infection, including ODI. Further data are needed to confirm SXT efficacy as an alternative oral regimen in BJIs.

Introduction

Bone and joint infections (BJIs) are a real concern in the context of an increase of orthopedic device implantations in an aging population with comorbidities. In addition to surgery, adequate antimicrobial therapy is required to efficiently treat BJIs [1]. Rifampicin is deemed to be the best antibiotic active against Gram positive cocci (GPC) in case of BJI, especially due to Staphylococcus spp., in association with another antimicrobial agent [2,3]. One drawback with rifampicin is the frequent gastrointestinal side effects and the interaction with the p450 cytochromes, in particular in polymedicated elderly patients. Likewise, fluoroquinolones (FQ) are recommended in combination with rifampicin in staphylococcal BJI, or alone in infections due to Gram negative bacilli (GNB) [4-6]. This makes them particularly attractive due to a broad spectrum of activity with good bone diffusion and the possibility of oral administration [2]. Moreover, FQs have been shown to be as effective as intravenous beta-lactams for the treatment of osteomyelitis [7,8]. Thus, FQs took a central place in the treatment of BJIs with a high rate of success well-known since the 1990s [9]. However, in the last decades, resistance to FQs became increasingly prevalent [10]. In addition, a major drawback of prolonged FQ administration is the selection of Extended-Spectrum Beta-Lactamase (ESBL) producing Enterobacteriaceae [11] and their risk of induced-tendinitis but also neurotoxicity (around 2%) [12]. Another drawback of FQ therapy is the subsequent risk of Clostridioides difficile infection, in particular in the elderly. Therefore, alternative drugs to FQs are needed.

Cotrimoxazole (Sulfamethoxazole-Trimethoprim, SXT), is an inhibitor of folinic acid synthesis and has bacteriostatic activity against susceptible bacteria. SXT has some interesting characteristics for the treatment of BJIs. First, SXT is effective against both gram positive and gram negative bacteria, including MRSA [13-16]. Second, its bone diffusion is deemed to be adequate when high posologies are used, including when orally administered [17,18]. The efficacy of SXT in BJIs was first reported in the early 1970s [19]. Recent studies reported its efficacy especially in association with rifampicin in staphylococcal BJI [20,21], leading to the suggestion of SXT as an alternative to FQs in staphylococcal BJIs in the American, British and French guidelines [22-24]. Despite these encouraging data, SXT use remains limited, partly because of the related risk of adverse events, in particular cutaneous rash and haematotoxicity but also renal and hepatic impairment [25]. Therefore, new data to evaluate the efficacy and safety of SXT in BJIs are necessary, especially when other recommended oral agents cannot be prescribed.

The main objective of the study was to evaluate the effectiveness of SXT in BJIs after day 90. The secondary objective was to assess SXT-related adverse events.

Methods

Setting

A retrospective study was conducted in 2 reference centers for BJIs treatment located in the Greater Paris area, France (Ambroise Paré Hospital, Boulogne-Billancourt, and Raymond Poincaré Hospital, Garches). Those 2 teaching hospitals share common staff with weekly pluridisciplinary meetings with an infectious disease specialist, an orthopedic surgeon, a microbiologist and a pharmacist. In our local guidelines, patients undergoing surgery for a BJI were administered empiric broad spectrum intravenous antimicrobial therapy post-operatively combining daptomycin and piperacillin-tazobactam in case of orthopedic device infection (ODI), or vancomycin and piperacillin-tazobactam in case of a native BJI, as appropriate. All adult patients admitted for a BJI in orthopedics and treated with SXT from January 2013 to April 2018 were enrolled in the study. Those centers managed 1568 BJIs during this period. Exclusion criteria were: age under 18 years, being infected by a microorganism non-susceptible to SXT, duration of SXT prescription of less than 10 days prescribed for the drainage of an abscess and a suppressive antimicrobial therapy (more than a year of therapy) or declining to participate in the study.

Criteria for the diagnosis of acute bone and joint infection were based on clinical signs and symptoms of bone and joint infection associated with a positive bacteriological examination of blood, bone or joint fluid samples.

Success was defined as the absence of local or systemic signs of infection, including delayed wound healing recorded in the medical chart, and a statistical diminution of the CRP value between admission and last follow-up consultation associated with absence of relapse. Cases who did not meet above-mentioned criteria were classified as “failure”.

Salvage therapy was defined by the inability to use a recommended regimen for the treatment of BJIs, notably a combination therapy with fluoroquinolones and rifampin for staphylococcal infection, due to a resistance mechanism or intolerance. In case of polymicrobial infection or potentially resistant organism (such as ESBL or cephalosporinase producing organisms), SXT was prescribed in combination therapy mainly to prevent the emergence of fluoroquinolones resistant mutants or broaden the antibiotic spectrum.

Multidrug-resistant organisms included ESBL-producing Enterobacteriaceae and/or methicillin-resistant Staphylococcus aureus strains.

Data collection

The following data were collected from patient’s medical charts:

Patient characteristics: age, sex, diabetes, smoking habits, peripheral vascular disease, allergy to antibiotic, Charlson score at admission, number of previous surgeries,

Infection characteristics: orthopedic device (OD) (prosthetic joint, osteosynthesis, vertebral OD), site of infection, mono or polymicrobial infection, microorganism and mechanism of resistance, concomitant bacteremia, C-reactive protein (CRP) at diagnosis,

Treatment characteristics: surgery (device retention, removal or replacement), empiric antimicrobial therapy, duration of intravenous antibiotic therapy, SXT use, route of administration, dosing and duration of treatment, mono or combination therapy with associated drugs.

Outcomes were evaluated at day (D) 7 after the surgery, D45 and D90. The occurrence of death, adverse event, length of stay (LOS) and CRP at the last follow-up was collected. Later events were documented by telephone interviews.

Statistical analysis

Descriptive results were expressed using median and interquartile range (IQR) for the continuous variables when appropriate, and in number with percentage for the categorical variables. Analyses were performed using Excel 2010 (Microsoft Corporation, Redmond, WA). Student’s t-test was performed to analyze continuous data using GraphPad Prism v.7.0 (GraphPad Software Inc., La Jolla, CA). Statistical significance was defined as p<0.05.

Compliance with ethical standards and approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

The local Ethics Committee was contacted and there was a waiver of any need for consent, linked to the retrospective nature of this study, since data have already been collected and thereafter data analyzed anonymously.

Results

Study population and infection characteristics

Overall, 124 patients were screened and are presented in the flow-chart (Fig 1). Fifty-one patients were included in the study which represents 3.2% of all the admission for BJI during this period. The median LOS was 10 days (IQR 8–17). Population and infection characteristics are detailed in Table 1. The sex ratio was 1 and the mean (± standard deviation (SD)) age was 60 ± 20 years. Twenty-one (41%) infections were polymicrobial, involving 2 to 4 bacterial species. BJIs were caused by Gram positive (GP) bacteria only (53%; n = 27), Gram negative (GN) bacteria (18%; n = 9) and 29% both GP and GN bacteria (n = 15). GPC included 39% coagulase-negative Staphylococci (CoNS) (n = 20), 27% methicillin-susceptible Staphylococcus aureus (MSSA) (n = 14) and 12% methicillin-resistant S. aureus (MRSA) (n = 6). GNB included 43% Enterobacteriaceae (n = 22) and 10% non-fermenter GNB (n = 5). Enterobacteriaceae were cephalosporinases producing species in 27% (n = 14) of cases and one case of ESBL-producing E. coli. Microorganisms are detailed in Table 2.

Fig 1

Flow chart of patients included in the study.

Table 1

Population and infection characteristics.

	Total(N = 51)		Success(N = 40)		Failure(N = 11)		P
Population characteristics
Male, n(%)	25	(49)	20	(50)	5	(45)	NS
Age (years), median (IQR)	60	(44–77)	60	(44–76)	70	(42–76)	NS
Comorbidities, n(%)	29	(57)	24	(60)	5	(45)	NS
Diabetes, n(%)	11	(22)	9	(23)	2	(18)	NS
Smoking habits, n(%)	21	(41)	18	(45)	3	(27)	NS
Peripheral artery disease, n(%)	8	(16)	6	(15)	2	(18)	NS
Charlson score, median (min-max)	3	(0–8)	3	(0–8)	4	(0–8)	NS
Previous surgery, median (min-max)	1	(0–4)	1	(0–4)	1	(0–4)	NS
Allergy, n(%)	5	(10)	3	(8)	2	(18)	NS
Beta-lactam, n(%)	3	(6)
Fluoroquinolone, n(%)	2	(4)
Infection characteristics
CRP at diagnosis (mg/l), median (IQR)	77	(26–111)	67	(21–108)	78	(59–133)	NS
Chronic infection, n(%)	40	(78)	31	(78)	9	(82)	NS
Type of infection
ODI, n(%)	39	(76)	29	(73)	10	(91)	NS
PJI, n(%)	28	(55)	20	(50)	8	(73)	NS
Osteosynthesis infection, n(%)	10	(20)	9	(23)	1	(9)	NS
Vertebral ODI, n(%)	1	(2)	0	(0)	1	(9)	NS
Osteomyelitis, n(%)	6	(12)	5	(13)	1	(9)	NS
Arthritis, n(%)	5	(10)	5	(13)	0	(0)	NS
Spondylodiscitis, n(%)	1	(2)	1	(3)	0	(0)	NS
Site of infection
Lower limb, n(%)	42	(82)	32	(80)	10	(91)	NS
Knee, n(%)	13	(25)
Hip, n(%)	12	(24)
Leg, n(%)	8	(16)
Ankle/foot, n(%)	7	(14)
Femur, n(%)	2	(4)
Upper limb, n(%)	7	(14)	7	(18)	0	(0)	NS
Elbow, n(%)	5	(10)
Shoulder, n(%)	2	(4)
Vertebral, n(%)	2	(4)	1	(3)	1	(9)	NS

CRP, C-reactive protein; ODI, orthopedic device infection; PJI, prosthetic joint infection.

Table 2

Microbiological characteristics.

	Total (N = 51)		Success(N = 40)		Failure(N = 11)		P
Polymicrobial, n(%)	21	(41)	16	(40)	5	(45)	NS
GP and GN bacterial infection, n(%)	15	(29)	12	(30)	3	(27)	NS
CGP, n(%)	41	(80)	33	(83)	8	(73)	NS
CoNS, n(%)	20	(39)
MSSA, n(%)	14	(27)
MRSA, n(%)	6	(12)
Streptococcus, n(%)	4	(8)
Enterococcus, n(%)	4	(8)
GNB, n(%)	24	(47)	18	(45)	6	(55)	NS
Enterobacteriaceae, n(%)	22	(43)
Enterobacter sp, n(%)	10	(20)
Escherichia coli, n(%)	5	(10)
Klebsiella sp, n(%)	3	(6)
Morganella morganii, n(%)	3	(6)
Serratia sp, n(%)	3	(6)
Proteus mirabilis, n(%)	2	(4)
Group 3 Enterobacteriaceae, n(%)	14	(27)	9	(23)	5	(45)	NS
Non fermental BGN, n(%)	5	(10)	4	(10)	1	(9)	NS
Pseudomonas aeruginosa, n(%)	2	(4)
Stenotrophomonas maltophilia, n(%)	2	(4)
Acinetobacter sp, n(%)	1	(2)
Other, n(%)	4	(8)	3	(8)	1	(9)	NS
Propionibacterium acnes, n(%)	2	(4)
Corynebacterium sp, n(%)	2	(4)
MDR bacteria, n(%)	7	(14)	5	(13)	2	(18)	NS
MRSA, n(%)	6	(12)
ESBL, n(%)	1	(2)
Bacteraemia, n(%)	1	(2)	1	(3)	0	(0)	NS

GP, gram positive; GN, gram negative; CGP, cocci gram positive; GNB, gram negative bacilli; CoNS, coagulase-negative Staphylococci; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus; MDR, multi-drug resistant; ESBL, extended-spectrum beta lactamase. Of note, the total number of microorganisms exceeds 100% as there are polymicrobial infections.

Overall, 25 patients had organisms which were resistant to fluoroquinolones and 5 patients were considered intolerant to the oral agents, notably among elderly patients related to confusional states.

Surgical management

All patients underwent surgery during the course of therapy. The procedure consisted of debridement on native joint in 12 cases (24%) debridement and implant retention in 11 cases (22%) and debridement with OD removal in 28 cases (55%) (Table 3). Eight ODIs presented acutely versus 31 chronic ODIs. Debridement and implant retention was performed in 26% (n = 8) of cases vs debridement with OD removal in 74% (n = 23).

Table 3

Surgical management and antimicrobial regimen.

	Total (N = 51)		Success(N = 40)		Failure(N = 11)		P
Surgical management
Surgery, n(%)	51	(100)	40	(100)	11	(100)	NS
Debridement on native joint, n(%)	12	(24)	11	(28)	1	(9)	NS
Debridement and implant retention, n(%)	11	(22)	9	(23)	2	(18)	NS
Debridement with OD removal, n(%)	28	(55)	20	(50)	8	(73)	NS
1 stage change, n(%)	19	(68)	14	(35)	5	(45)	NS
2 stages change, n(%)	1	(4)	1	(3)	0	(0)	NS
No implantation, n(%)	8	(29)	5	(13)	3	(27)	NS
Medical management
Empiric antiimicrobial therapy, n(%)	50	(98)	39	(98)	11	(100)	NS
Beta-lactam, n(%)	49	(96)	38	(95)	11	(100)	NS
Piperacillin-tazobactam, n(%)	43	(84)
Other, n(%)	6	(12)
Anti-MRSA ATB, n(%)	46	(90)	36	(90)	10	(91)	NS
Vancomycin, n(%)	23	(45)
Daptomycin, n(%)	23	(45)
Other, n(%)	4	(8)	3	(8)	1	(9)	NS
Intra-venous ATB duration (days), median (IQR)	6	(5–7)	6	(5–7)	6	(5–8)	NS
SXT prescription modalities
Daily dose, n(%)
800/160mg bid, n(%)	31	(61)	25	(63)	6	(55)	NS
800/160mg tid, n(%)	20	(39)	15	(38)	5	(45)	NS
Oral intake, n(%)	51	(100)	40	(100)	11	(100)	NS
Number of associated ATB, n(%)
1, n(%)	43	(84)	36	(90)	7	(64)	NS
≥2, n(%)	8	(16)	4	(10)	4	(36)	NS
Associated ATB in dual therapy, n(%)
FQ, n(%)	17	(40)	14	(35)	3	(27)	NS
RMP, n(%)	14	(33)	12	(30)	2	(18)	NS
Other, n(%)	12	(28)	10	(25)	2	(18)	NS
Oral ATB duration (days), median (IQR)	45	(40–45)	45	(40–45)	37	(34–44)	NS
Total ATB duration (days), median (IQR)	47	(45–51)	48	(45–51)	42	(41–50)	NS

OD, orthopedic device; ATB, antibiotic; MRSA, methicillin-resistant Staphylococcus aureus; SXT, Sulfamethoxazole-trimethoprim; RMP, rifampicin; FQ, fluoroquinolone.

Antimicrobial regimens

Median duration of first-line IV treatment was 7 days (ranging from 5 to 10 days).

All patients received an oral regimen with SXT as part of a combination therapy, with 43 (84%) dual therapy and 8 (16%) tritherapy or more (detailed in Table 3). Of the eight patients treated with three or more antimicrobial agents, 88% were polymicrobial (n = 7) involving both GPC and GNB in 38% (n = 3).

The associated drugs used in dual therapy were mainly FQ or rifampicin (72%, n = 31). Among patients treated with a dual therapy including a FQ (n = 17), 11 (65%) were due to a cephalosporinase producing Enterobacteriaceae. Conversely, 12 (28%) cases received neither rifampicin nor FQ in bitherapy with SXT. The regimen included beta-lactams (n = 4) (amoxicillin-clavulanic acid (n = 3) and cefepime (n = 1)), clindamycin (n = 4), daptomycin (n = 2), vancomycin (n = 1) or linezolid (n = 1).

Outcomes

The median duration of follow-up was 126 days (IQR 99–185); 5 (9.8%) patients were lost to follow-up at D90, including 2 cases before D45.

The median CRP level at the last follow-up was 10 mg/L (IQR 2–24) and lower than at the admission (see Table 1) (p<0.0001). In our center, the CRP value was considered normal at a value of ≤5 mg/L and was found in 21 (41.2%) patients at the last follow-up consultation.

Considering those who were lost to follow-up as failures, outcomes were favorable at D7 in 98% (n = 50), at D45 in 88.2% (n = 45) and at D90 in 78.4% (n = 40). If we exclude those who were lost to follow-up from the final analyses (best-case scenario), outcomes were favorable at D7 in 98% (n = 50/51), at D45 in 91.8% (n = 45/49) and at D90 in 87.0% (n = 40/46). Outcomes at D90 depending on the drug used in combination therapy with SXT were comparable between groups (p = 0.97) and are detailed in Fig 2.

Fig 2

Outcomes at day 7, day 45 and day 90, overall (2A) and at day 90 depending on the drug associated with SXT in dual therapy (2B).

In univariate analyses, infection with a cephalosporin producing Enterobacteriaceae (n = 14) was not significantly associated with a worse outcome at D90 with a 64.3% (n = 9) cure rate vs other groups 83.8% (n = 31) (p = 0.15). Of note, 78.6% (n = 11) were treated with a dual therapy containing SXT/FQ.

No patient died nor was admitted to intensive care unit in the course of treatment. Twenty-one patients (41%) had a limitation in their function at the end of follow-up.

Adverse events

Adverse events were reported in 4 (8%) patients, with a median time of 21 days (IQR 20–30) from SXT introduction. Adverse events consisted of a mild hepatitis (values up to 3 times above the normal), a short duration watery diarrhea, a cutaneous maculopapular skin rash and an isolated fever in 1 case each. No renal failure was diagnosed during follow-up. SXT was interrupted in 6% (n = 3): 1 patient had replacement with a switch to another antimicrobial therapy (n = 1) and 2 antibiotic discontinuations were noted. Three of them were lost to follow-up at D90.

Discussion

This retrospective study documents numerous patients treated with a combination therapy based on SXT for the treatment of a polymicrobial BJI (41%). We observed a favorable outcome at D90 in 78.4%; nevertheless adverse events led to SXT discontinuation in 6% of patients. It is noteworthy that when used in dual therapy, the second agent combined with SXT did not impact the overall success rate.

A success rate of less than 80% can appear disappointing but it rises up to 87% in the best case scenario. This rate is gratifying if we consider the higher proportion than usual of these particular prosthetic joint infections due to polymicrobial and Gram-negative bacteria [10,26]. Moreover it concerns elderly and fragile patients with frequent comorbidities who underwent previous surgeries which failed initial therapy (as illustrated in Table 1) and therefore required the expertise of a reference center.

This rate of favorable outcome is slightly higher than previously reported in the literature in GPC and GNB BJIs treated with SXT. Indeed, Fica et al. reported a success rate of 61% (n = 23) with 9 failures requiring surgery [27]. In another study regarding early ODI due to GCP and GNB, Torenero et al. support the fact that SXT is inappropriate due to a high rate of failure but in a small sample size of 7 patients (including 5 due to GPC and 2 to GNB) [28].

Our results are similar to those more recently reported in GPC BJIs. Euba et al. showed that SXT in combination with rifampicin was as effective as intravenous cloxacillin in the treatment of 28 chronic staphylococcal osteomyelitis, with 88.9% success in intention to treat and 91.7% in per protocol analyses [29]. Moreover, Nguyen et al. reported a success rate of 78.6% at the end of the treatment and 76.9% at 2 years. This study was conducted among 26 patients with a BJI treated with SXT in association with rifampicin. This latter study showed similar outcomes using this regimen based on SXT versus a combination of rifampicin plus linezolid [30]. Likewise, Harbarth et al. described a 85.7% success rate (n = 75) using SXT in association with rifampicin for the treatment of MRSA BJI in comparison with 55.6% when using linezolid alone [31]. Finally, in pediatrics, Messina et al. reported a success rate of 100% (n = 20) using a monotherapy of SXT for the treatment of acute Staphylococcus aureus osteomyelitis [32].

Of note, one major point pleading for the use of SXT over FQ is that MRSA strains seem to remain susceptible to SXT even after a SXT exposure [33]. However, physicians should be wary that there is a possible risk of emergence of resistance against rifampicin when prescribed in dual therapy with SXT, despite a combination therapy [34]. Nevertheless, it should be noted that those concerns are based on in vitro data and must be discussed in the light of clinical findings.

In addition, data are scarce concerning GNB prosthetic joint infections, which represents 15% of BJIs and are known to be difficult to treat [35]. Nevertheless, our data did not show any statistical differences in terms of outcomes between cephalosporinase producing Enterobacteriaceae and the other cases, likely because of an underpowered dataset (n = 51). A combination therapy of SXT with a FQ in these patients was associated with a favorable outcome in 82.3%. Although the systemic use of a combination therapy against GNB including cephalosporinase producers might have been overcautious, it may have helped to preserve FQs acquiring resistance.

In addition, median duration of treatment was 6 weeks which is generally compliant according to the French guidelines [22] and promoting the appropriate use of antibiotic duration. In such prolonged therapy, an efficient oral regimen can be helpful to reduce LOS. Indeed, our reported LOS was quite short with a median of 10 days. Previously published studies have also reported a diminution of the LOS for BJI while using SXT [27,30]. Likewise, although costs have not been studied, some literature has already reported a diminution of costs when prescription included SXT [26,30,36].

Even if the reason to prescribe SXT over other molecules was not clearly stated in the medical records, most of the prescriptions were supported by the resistance to either FQ or rifampicin. Indeed, allergy was not the main reason for prescribing SXT since only a few patients presented allergy to FQ and none to rifampicin.

Overall, SXT’s broad spectrum activity could be of interest in various populations, including elderly patients with polymicrobial infections, previously exposed to usual classes of antibiotics (i.e. FQ and rifampicin).

Interestingly, the doses of SXT we used were frequently lower than recommended by the French (3200/640mg) and US guidelines (8 mg/kg of trimethoprim) [22,23], but also lower than the ones reported in previous cohorts of BJIs treated with SXT [27,29-31]. This can be explained by the fact that physicians did not want to use high doses considering the elderly population with an increased risk of side effects. Although it can be argued that lower doses can be responsible for antibiotic selective pressure, our prescriptions were performed as combination therapy, thereby reducing the potential risk of the appearance of mutants.

SXT is responsible for various adverse events such as cutaneous rash, gastrointestinal disorders, hepatitis, cytopenia [25] or acute renal failure [37,38]. In our study, adverse events were reported in only 8% of patients, leading to SXT interruption in 6%. A similar rate was reported in previous studies concerning staphylococcal BJI with 12% adverse events and 7% SXT discontinuation due to adverse events [29,31]. Likewise, Valour et al. reported a comparable rate of 15% of adverse events in patients treated with various other antibiotics for methicilllin-susceptible Staphylococcus aureus BJI [39]. However, Nguyen et al. reported a higher rate of 46% of adverse events using SXT [30]. These results can partly be explained by the long mean duration of therapy of 17.8 weeks. Likewise, Fica et al. reported 43% of SXT discontinuation mainly due to hyperkalemia in patients treated with drugs active against the renin-angiotensin system [27]. Those adverse events must be balanced with the new alert of aortic aneurysm and dissection due to the prolonged used of fluoroquinolones (>14 days) [40], that is a serious threat to consider in such population of elderly and comorbid patients suffering from BJIs.

Finally, our study presents some limitations. First, it is a retrospective study with a relatively limited sample size; thereby its results might not be extrapolated to other healthcare facilities. Second, the infections included are heterogeneous with OD and native BJI caused by GPC and GNB infections. However, it reinforces the usefulness of SXT when clinicians are dealing with polymicrobial infections. Third, we faced a substantial number of patients lost to follow-up despite a relatively short median duration of follow-up for a BJI, considering that infection cure is usually defined after a one-year follow-up. However, individuals who were lost to follow-up were interpreted as failures to avoid an over-estimation of the success rate in final analyses and this is what we observed in real-life.

Conclusion

Cotrimoxazole appears to be effective for the treatment of BJIs. Its broad spectrum activity makes it particularly interesting in polymicrobial infections with GPC and GNB as illustrated in our work. It can prove helpful as a salvage therapy when the preferred combination therapy with FQ or rifampicin is unusable, but also in case of deadlock situations requiring intravenous and prolonged therapy. Although the described rate of reported adverse events was acceptable, physicians should be wary that most patients who experienced adverse events required discontinuation of their therapy. We believe our work will encourage reference centers taking into consideration the use of SXT. Further prospective data are needed to confirm SXT efficacy as an alternative regimen in common BJIs.

16 Aug 2019

PONE-D-19-17215

Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJI)

PLOS ONE

Dear Dr. Davido,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Please address all the peer reviewer comments . Some substantive issues have been raised with which I agree. and need to be addressed. In addition there are several Editorial comments that need to be addressed which are outlined below.

It is not clear how patients were selected given that many patients may have been referred and some were treated with TMP-SMX . Please clarify what proportion of patients were treated with this agent  aby nd how the selection was made ie a convenience sample or some other method.

The definitions need more details and especially "diminution of CRP - was a normal value required ? Please be as objective as possible.

Please clarify within the manuscript the number of cases considered resistant or intolerant  to the usual recommended regimen of a FQ  plus rifampin -and then reconcile why in some cases TMP-SM|X was combined with a FQ..

There were a large number of patients excluded due to " no data" which deserves more explanation ie was it missing or not available ?

Please indicate if the Ethics Committee was contacted and there was a waiver of any need for consent.

The susceptibility of the organisms listed should be provided to both the FQs and TMP-SMX.

Define multidrug resistant.

Add something to the legend in Table 2 about the microbes and that they do not add to 100% given the multiple isolates.

Please explain  why some cases had dual therapy with both a FQ and TMP-SMX. What was the rationale ?

Please tell us the normal values for the CRP and how many patients achieved a normal CRP.

As mentioned by the peer reviewer the use of intention to treat and per protocol is usually reserved for RCTs so please rephrase this or if some other terms are used explain and introduce them in the Methods.

Please define what represents hepatitis, diarrhea and cutaneous rash in more explicit terms so the readers can determine what is mean by the terms. .

There are a large number of typographical and grammatical errors which need correcting throughout the manuscript.

The references have many errors and there are case issues which are not consistent in the listing of the references and no Latin terms have italics eg names of microbes

==============================

We would appreciate receiving your revised manuscript by Sept 30, 2019. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Kind regards,

John Conly, MD

Academic Editor

PLOS ONE

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**********

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Reviewer #1: This is an interesting observational paper but the methods and limited data don't allow confidence in the conclusions proposed. The majority of patients received dual drug therapy which makes conclusions about the efficacy of cotrimoxazole alone for these infections questionable. A 10% loss to follow-up could substantially affect success rates and I am concerned about an additional 9 patients excluded due to duration of therapy less than 10 days and 5 excluded due to suppressive therapy. The reasons for therapy less than 10 days are not provided - was this a reflection of treatment failure? How it was determined in a retrospective chart review that treatment was for suppression rather than curative therapy is also not made clear either. These 15 patients could represent additional treatment failures but this can't be determined from the information available.

Success criteria are listed as "the absence of local or systemic sign of infection, including

delayed wound healing, and the diminution of CRP and the absence of relapse". It isn't clear how in a retrospective chart review a determination was made about the "local or systemic signs of infection" or "delayed wound healing". What was the quality of documentation on these features in the charts reviewed? How was relapse defined? How subjective was this analysis? Were there specific definitions based on what was found in the charts for these criteria?

The small sample size combined with 10% loss to follow-up and the 15 excluded patients above combined with the retrospective nature of the review and possibly very subjective criteria for success when determined in a chart review make any conclusions suspect.

The conclusion states "SXT appears to be effective for treatment of BJI as a salvage therapy" and in description salvage therapy was referred to as "the impossibility to use recommended regimen for the treatment of BJI, notably a combination therapy with fluoroquinolones and rifampin, either due to a resistance mechanism or an intolerance."

The paper fails to provide adequate data to explain why cotrimoxazole might have been chosen in these patients and specifically states that "allergy was not the main reason for prescribing SXT since only a few patients presented allergy to FQ and none to rifampicin" and further suggests that the reason cotrimoxazole was chosen was not necessarily stated in the medical records. Normally salvage therapy implies a failed trial of usual therapy before a switch to the "salvage" therapy. This is not clarified in the paper. Neither the definition of salvage therapy nor the description of why cotrimoxazole was chosen are appropriate to reach the conclusion stated.

Use of terms "intention to treat" and "per protocol" in description of the analysis is inappropriate as it implies a prospective randomized experimental design rather than a retrospective review. Therre was no "protocol" when the patients were started on therapy.

**********

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Reviewer #1: Yes: Andrew L S Pattullo

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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21 Aug 2019

First, we would like to thank the editor and the reviewer for their relevant suggestions and comments that have been considered and improved the overall revised manuscript. We hope you will find this version clarified and useful for the readers.Please find attached the rebuttal letter with the correction we made in the revised manuscript.

Regards,

Submitted filename: PONE.docx

Click here for additional data file.

11 Sep 2019

[EXSCINDED]

PONE-D-19-17215R1

Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs)

PLOS ONE

Dear Dr. Davido,

Thank you for submitting your revised manuscript to PLOS ONE which has been substantially improved . However there remain a number of issues, mainly grammatical and syntax that need correcting. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised below.

==============================

Abstract

- Should be “ a broad spectrum of activity…”

- The sentences “ We noted 76% of  orthopedic device infection (ODI). Infections were mostly polymicrobial (41%), including 47 % of gram-negative bacilli (GNB). “ and “ The drug associated with SXT was not an independent factor of success (p=0.97).”  are grammatically poor and need correcting

Prefer wording of  “ alternative oral  regimen in BJIs.” In the last sentence

Introduction

Better wording would be as follows in the sentences containing the following phrases

“ ….concern in the  context of an increase ….”

“ to efficiently treat BJIs “

“  p450 ctyochromes “

“ a  major drawback of prolonged FQ administration is the”

Therefore, alternative drugs to FQs are needed. (remove the remainder of the sentence ie if we want to apply a case

“The  efficacy of SXT  in BJIs was first reported in the early  early 1970s

“ …………when other  recommended oral  agents cannot be prescribed.”

Please use italics for Latin terms eg organism names throughout the manuscript ie Staphylococcus species

Methods

Better wording would be as follows in the sentences containing the following phrases

“ ………..were administered empiric broad spectrum intravenous

antimicrobial therapy post-operatively combining ……”

All adults patients should be “ all adult patients “

Please spell out the abbreviated ODI in full for first time use in the body of the manuscript

Should be “……..or systemic signs of infection …” rather than sign

Correct to  “ ….wound healing recorded in the medical chart,……”

Should be “ diminution of the  CRP value…. “

Should be “ … defined by the inability to use a recommended ….”

Should be “ … or potentially resistant organism (such as ESBL or

cephalosporinase producing  organisms…..   broaden the antibiotic spectrum.

Should be “ ESBL-producing Enterobacteriaceae and/or ….”

Should be “ empiric” rather than empirical

Should be “The local Ethics Committee was contacted ………”

Results

Should be “ patients were included in the study which represents …. “

Should be “…..(n=14) and 12% methicillin-resistant…”

Should be worded better as  “ Overall, 25 patients had organisms which were resistant to fluoroquinolones and 5 patients  were considered intolerant to the oral agents,  notably among elderly patients related to confusional states. “

Should be “……..surgery during  the course of therapy.”

Should be “ ……………. The procedures consisted of …….”

Should be “ ………….was performed in 26%  (n=8) of cases vs debridement….”

Should be “…. Table 3. Surgical management and antimicrobial regimen.’

Same for the subtitle – better as Antimicrobial Regimens “

Please use another term other than “relay” for the use of an oral regimen

Should be “In our center, the CRP value was considered normal at a value of  ≤5

mg/L and was found in 21 (41.2%) patients at the last follow-up consultation.”

Should be “………….not significantly associated……………..”

Should be “Adverse events consisted of  a mild hepatitis (values up to 3 times

above the normal), a short duration watery diarrhea,  a cutaneous maculopapular skin

rash and an isolated fever in 1 case each. No renal failure was diagnosed during follow-up.

SXT was interrupted in 6% (n=3): 1 patient had replacement with a switch to another antimicrobial

therapy (n=1) and 2 antibiotic discontinuations were noted. “

Discussion

Better wording would be as follows in the sentences containing the following phrases

Should be “ This retrospective study documents numerous patients treated with a

combination therapy based on SXT for the treatment of a polymicrobial BJI”

Should be “ ………. can appear disappointing but it rises up to 87%  in the best case scenario.”

Should be “ This rate is gratifying  if we consider the higher proportion than usual of these particular prosthetic joint infections due to polymicrobial and Gram negative bacteria.”

Should be “  Moreover it concerns elderly and fragile patients with frequent comorbidities who underwent previous surgeries which failed initial therapy and therefore required the expertise of a reference center.”

Should be “ This latter study showed similar  outcomes using this regimen based on SXT versus………..”

Should be “ In addition, median duration of treatment was 6 weeks which is generally compliant according to the French guidelines [22] and promoting the appropriate use of antibiotic duration.”

Should be “ Likewise, although costs have not been studied, some  literature has already reported a diminution of costs when…….” And there should be a reference added to support .

The phrase “………but also than the ones reported in previous cohorts of BJI treated with SXT………… “ is missing something – please correct

Should be “ ………. For  antibiotic selective pressure,”

Eliminate the sentence “A particular attention to renal function and potassium level must be paid in these patients especially when using high dosing of SXT. “ It adds very little and helps to tighten the manuscript.

Conclusion

Eliminate “……….in common daily encountered practice………….”

References

There are a few items to correct with respect to case in the references eg the last 2 and other refs have the title of the paper all in capital letters – please correct

==============================

We would appreciate receiving your revised manuscript by %Sept 30, 2019. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

John Conly, MD

Academic Editor

PLOS ONE

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

23 Sep 2019

Dear Dr. Davido,

Thank you for submitting your revised manuscript to PLOS ONE which has been substantially improved . However there remain a number of issues, mainly grammatical and syntax that need correcting. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised below.

==============================

First, we would like to thank the editor (John Conly) for his finesse and suggestions of clarification. All the comments have been taken into consideration. We believe this version is now ready for publication.

Abstract

- Should be “ a broad spectrum of activity…”

- The sentences “ We noted 76% of orthopedic device infection (ODI). Infections were mostly polymicrobial (41%), including 47 % of gram-negative bacilli (GNB). “ and “ The drug associated with SXT was not an independent factor of success (p=0.97).” are grammatically poor and need correcting

We rephrased it as follows: “Gram-negative bacilli (GNB) were involved in 47% of BJIs (n=24). Moreover, they were often polymicrobial infections (41%)” And

“The second agent combined with SXT was not an independent factor of favorable outcome (p=0.97).”

Prefer wording of “ alternative oral regimen in BJIs.” In the last sentence

Corrected

Introduction

Better wording would be as follows in the sentences containing the following phrases

“ ….concern in the context of an increase ….”

“ to efficiently treat BJIs “

“ p450 ctyochromes “

“ a major drawback of prolonged FQ administration is the”

Therefore, alternative drugs to FQs are needed. (remove the remainder of the sentence ie if we want to apply a case

“The efficacy of SXT in BJIs was first reported in the early early 1970s

“ …………when other recommended oral agents cannot be prescribed.”

Please use italics for Latin terms eg organism names throughout the manuscript ie Staphylococcus species

Corrected

Methods

Better wording would be as follows in the sentences containing the following phrases

“ ………..were administered empiric broad spectrum intravenous

antimicrobial therapy post-operatively combining ……”

All adults patients should be “ all adult patients “

Please spell out the abbreviated ODI in full for first time use in the body of the manuscript

Corrected

Should be “……..or systemic signs of infection …” rather than sign

Correct to “ ….wound healing recorded in the medical chart,……”

Should be “ diminution of the CRP value…. “

Should be “ … defined by the inability to use a recommended ….”

Corrected

Should be “ … or potentially resistant organism (such as ESBL or

cephalosporinase producing organisms….. broaden the antibiotic spectrum.

Should be “ ESBL-producing Enterobacteriaceae and/or ….”

Should be “ empiric” rather than empirical

Should be “The local Ethics Committee was contacted ………”

Corrected

Results

Should be “ patients were included in the study which represents …. “

Should be “…..(n=14) and 12% methicillin-resistant…”

Should be worded better as “ Overall, 25 patients had organisms which were resistant to fluoroquinolones and 5 patients were considered intolerant to the oral agents, notably among elderly patients related to confusional states. “

Should be “……..surgery during the course of therapy.”

Should be “ ……………. The procedures consisted of …….”

Should be “ ………….was performed in 26% (n=8) of cases vs debridement….”

Should be “…. Table 3. Surgical management and antimicrobial regimen.’

Same for the subtitle – better as Antimicrobial Regimens “

Corrected

Please use another term other than “relay” for the use of an oral regimen

We simply used the term oral regimen.

Should be “In our center, the CRP value was considered normal at a value of ≤5

mg/L and was found in 21 (41.2%) patients at the last follow-up consultation.”

Should be “………….not significantly associated……………..”

Should be “Adverse events consisted of a mild hepatitis (values up to 3 times

above the normal), a short duration watery diarrhea, a cutaneous maculopapular skin rash and an isolated fever in 1 case each. No renal failure was diagnosed during follow-up.

SXT was interrupted in 6% (n=3): 1 patient had replacement with a switch to another antimicrobial therapy (n=1) and 2 antibiotic discontinuations were noted. “

Corrected

Discussion

Better wording would be as follows in the sentences containing the following phrases

Should be “ This retrospective study documents numerous patients treated with a

combination therapy based on SXT for the treatment of a polymicrobial BJI”

Should be “ ………. can appear disappointing but it rises up to 87% in the best case scenario.”

Should be “ This rate is gratifying if we consider the higher proportion than usual of these particular prosthetic joint infections due to polymicrobial and Gram negative bacteria.”

Should be “ Moreover it concerns elderly and fragile patients with frequent comorbidities who underwent previous surgeries which failed initial therapy and therefore required the expertise of a reference center.”

Should be “ This latter study showed similar outcomes using this regimen based on SXT versus………..”

Should be “ In addition, median duration of treatment was 6 weeks which is generally compliant according to the French guidelines [22] and promoting the appropriate use of antibiotic duration.”

Corrected

Should be “ Likewise, although costs have not been studied, some literature has already reported a diminution of costs when…….” And there should be a reference added to support .

References were added, sorry for that. It was a problem with the software (Mendeley).

The phrase “………but also than the ones reported in previous cohorts of BJI treated with SXT………… “ is missing something – please correct

We rephrased it as follows: “but also than the ones reported in previous cohorts of BJIs treated with SXT which preconized high doses [27,29-31].”

Should be “ ………. For antibiotic selective pressure,”

Eliminate the sentence “A particular attention to renal function and potassium level must be paid in these patients especially when using high dosing of SXT. “ It adds very little and helps to tighten the manuscript.

Done

Conclusion

Eliminate “……….in common daily encountered practice………….”

Withdrawn.

References

There are a few items to correct with respect to case in the references eg the last 2 and other refs have the title of the paper all in capital letters – please correct

Corrected.

==============================

Submitted filename: rebuttal.docx

Click here for additional data file.

3 Oct 2019

PONE-D-19-17215R2

Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs)

PLOS ONE

Dear Dr. Davido,

Thank you for submitting your re-revised manuscript to PLOS ONE and carefully making the suggested edits and changes. . Unfortunately there remain a few areas where the text remains unclear and additional minor edits are  be required to ensure that the readership is able to completely follow the points that are being made. Therefore, we invite you to submit a further revised version of the manuscript that addresses the points raised during the most recent editorial review process.

==============================

Abstract

Should be "..... a broad spectrum of activity with adequate...."

"We noted 76% of orthopedic device infection (ODI)."  is a grammatically poor sentence and suggest to add the finding into the first sentence to avoid 2 short choppy sentences. Also in Table 1 you indicate that the age 60 was a median but you indicate a mean in the abstract - please correct  and also add in brackets the SD in the abstract ie " We analyzed 51 patients with a ?  mean ? median  age of 60 +> 20  (SD) years of which 76% presented with an orthopedic device infection (ODI).

Introduction

Should be "..... due to a broad spectrum of activity with good bone diffusion...."

Italics for Staphylococcus spp was forgotten to be added

The genus for Clostridium has been officially changed to Clostridioides so please change throughout the text where used but not the references

Should be " leading to the suggestion of SXT.... "

Methods

Should be ".....SXT use, route of administration..... " rather than currently shown as "SXT use: route of administration

The sentence ending with "associated drugs , "  ends with a  comma rather than a period.

Results

Note the discrepancy of use of a median age as in Table 1 as opposed to mean in the abstract - please correct

Discussion

Why do you say " .......... previous surgeries which failed failure  initial therapy ....." - please clarify or correct

Please correct the sentence " ...Harbarth et al described 85.7% of success ...." do you mean " a 85.7 % success rate...."

Prefer to say " "A combination of therapy of SXT with a  FQ in these patients was associated with a favorable outcome in 82.3% ." than as currently written.

".... preserve FQs from acquired resistance." should be "...... FQs acquiring resistance"

Something is incomplete or erroneous in the sentence ".... but also than the ones reported in previous  cohorts of BJIs treated with SXT which preconized...." - please correct

Should be plural ie "side effects "

Should be " SXT is responsible for various ..." rather than "... of various "

Should be " .... reinforces the usefulness of SXT"

Please rephrase " deadend situations " as not a scientific term

Should be plural ie    ".... physicians should .... "

Conclusion

Rather than ".... taking into consideration such molecule" why not just say " taking into consideration the use of SXT" since that is what your article suggests

**********

==============================

We would appreciate receiving your revised manuscript by Oct 21 2019.  When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

John Conly, MD

Academic Editor

PLOS ONE

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

4 Oct 2019

All the typo have now been corrected.

Thank you for this careful proofreading.

Abstract

Should be "..... a broad spectrum of activity with adequate...."

Already written as suggested.

"We noted 76% of orthopedic device infection (ODI)." is a grammatically poor sentence and suggest to add the finding into the first sentence to avoid 2 short choppy sentences. Also in Table 1 you indicate that the age 60 was a median but you indicate a mean in the abstract - please correct and also add in brackets the SD in the abstract ie " We analyzed 51 patients with a ? mean ? median age of 60 + 20 (SD) years of which 76% presented with an orthopedic device infection (ODI).

Thank you for the example. Actually median was=median so it is another way to show our results. Usually mean are commonly used in abstract, therefore we kept this presentation of our findings.

Introduction

Should be "..... due to a broad spectrum of activity with good bone diffusion...."

Corrected, thank you.

Italics for Staphylococcus spp was forgotten to be added

It’s now in italics, sorry for that mistake.

The genus for Clostridium has been officially changed to Clostridioides so please change throughout the text where used but not the references

Corrected.

Should be " leading to the suggestion of SXT.... "

Corrected.

Methods

Should be ".....SXT use, route of administration..... " rather than currently shown as "SXT use: route of administration

“:” has been changed to “,”

The sentence ending with "associated drugs , " ends with a comma rather than a period.

It was changed to a period as requested.

Results

Note the discrepancy of use of a median age as in Table 1 as opposed to mean in the abstract - please correct

Median is used in the Table 1 to illustrate IQR as we are dealing with a small sample size study. As clarified above, Median was equal to mean in our work.

Discussion

Why do you say " .......... previous surgeries which failed failure initial therapy ....." - please clarify or correct

Sorry for the duplicate and repeated word namely “failed failure”. Sentence was also clarified because it was referring to table 1: “previous surgeries which failed initial therapy (as illustrated in Table 1) and therefore required the expertise of a reference center.”

Please correct the sentence " ...Harbarth et al described 85.7% of success ...." do you mean " a 85.7 % success rate...."

Yes, sorry for that misunderstood. It is now corrected.

Prefer to say " "A combination of therapy of SXT with a FQ in these patients was associated with a favorable outcome in 82.3% ." than as currently written.

Thank you for the correction, which has been applied.

".... preserve FQs from acquired resistance." should be "...... FQs acquiring resistance"

Thank you for the correction, which has been applied.

Something is incomplete or erroneous in the sentence ".... but also than the ones reported in previous cohorts of BJIs treated with SXT which preconized...." - please correct

Sorry the word lower was missing in our sentence. We also shortened the sentence because the end was obvious, as follows: “the doses of SXT we used were frequently lower than recommended by the French (3200/640mg) and US guidelines (8 mg/kg of trimethoprim), but also lower than the ones reported in previous cohorts of BJIs treated with SXT”

Should be plural ie "side effects "

Corrected.

Should be " SXT is responsible for various ..." rather than "... of various "

Thank you for the correction, which has been applied.

Should be " .... reinforces the usefulness of SXT"

Sorry for the typo, it has been corrected.

Please rephrase " deadend situations " as not a scientific term

It has been changed to “deadlock” which can be used in scientific term, especially for antibiotics. (ie : https://www.ncbi.nlm.nih.gov/pubmed/24698433)

Should be plural ie ".... physicians should .... "

Corrected.

Conclusion

Rather than ".... taking into consideration such molecule" why not just say " taking into consideration the use of SXT" since that is what your article suggests

Thank you for the suggestion which clarified the conclusion and has been applied.

Submitted filename: rebuttal-R2.docx

Click here for additional data file.

7 Oct 2019

Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs)

PONE-D-19-17215R3

Dear Dr. Davido,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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Additional Editor Comments (optional):

Reviewers' comments:

9 Oct 2019

PONE-D-19-17215R3

Efficacy of cotrimoxazole (Sulfamethoxazole-Trimethoprim) as a salvage therapy for the treatment of bone and joint infections (BJIs)

Dear Dr. Davido:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr John Conly

Academic Editor

PLOS ONE