# Cirrhotic patients with bone and joint infections: A 10-year cohort study from a reference center

Vianney Tuloup, C. Doumit, Marie-Frédérique Lartigue, Louis-Romée Le

Nail, M. Lacasse, Adrien Lemaignen

► To cite this version:

Vianney Tuloup, C. Doumit, Marie-Frédérique Lartigue, Louis-Romée Le Nail, M. Lacasse, et al. Cirrhotic patients with bone and joint infections: A 10-year cohort study from a reference center. *Infectious Diseases Now*, 2025, 55 (6), pp.105099. 10.1016/j.idnow.2025.105099. hal-05194761

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Original article

# Cirrhotic patients with bone and joint infections: A 10-year cohort study from a reference center

V. Tuloup<sup>a,b,c,*</sup>, C. Doumit<sup>a</sup>, M.F. Lartigue<sup>d,e,f</sup>, L.R. Le Nail<sup>f,h,i</sup>, M. Lacasse<sup>g</sup>, A. Lemaignen<sup>f,g</sup>, among the Tours CRIOAC centre

## ARTICLE INFO

### Keywords:

- Drug-related problems

- Bone and Joint Infection

- Drug-drug interactions

- Cirrhosis

## ABSTRACT

**Introduction:** Bone and joint infections (BJI) require long-term and frequently high-dose antimicrobial treatment, often with heightened risk of drug-drug or drug-disease interactions. However, in some cases, notably regarding cirrhotic patients, these infections have yet to be adequately described. Cirrhosis is a major cause of end-stage chronic liver disease, entailing massive disorders in hepatic metabolism and a high rate of infections and comorbidities. We aimed to characterize the cirrhosis – BJI population treated over the last 10 years in our reference centre.

**Material and methods:** A descriptive monocentric retrospective study analysed routine care data extracted from our computer files. Patients labelled with a chronic hepatic disease were included. Biological, clinical and survival rate were researched. Drug-drug and drug-disease interactions were compiled and analysed using the exposure ratio, according to the Child-Pugh scale.

**Results:** Eighteen patients were included, for 28 presentations. Twelve were Child-Pugh B or C. Only two out of the 18 patients had their antimicrobial dosage adjusted. No patient who had not received the recommended dose adjustment was admitted to the emergency department or for consultation for an antibiotic-related adverse event. During the 1st year, two patients (11.1 %) required hospitalization for revision surgery. Neither relapsed a second time. Six patients (33.3 %) died during follow-up, but none of the deaths were related to infection (four cancers, two ischemic events).

**Conclusion:** We have shown that cirrhotic patients with BJI are infected with the same pathogens as the general population. Dose adjustments remain unclear, and further studies are required. BJI infections are particularly complex, and require enhanced multidisciplinary management.

## 1. Introduction

As the common end stage of various chronic liver diseases, cirrhosis is frequently associated with multiple comorbidities. The predominant etiologies—alcohol-induced, viral, or non-alcoholic steatohepatitis (NASH)-related cirrhosis—are all linked to increased susceptibility to infections due to immune dysfunction [1]. Additionally,

hypoproteinemia and hypoalbuminemia contribute to impaired wound healing, thereby increasing the likelihood of postoperative infections [2]. Cirrhotic patients often require polypharmacy, necessitating careful management due to significant hepatic metabolic dysfunction. However, guidelines for drug dose adjustments remain unclear [3–5]. Each pathophysiological alteration can further exacerbate cirrhosis, which remains irreversible due to the fibrotic nature of liver tissue.

<footnote><sup>a</sup> Pharmacy Department, CHU Tours, France</footnote>

<footnote><sup>b</sup> Pharmaceutical Science Faculty, Tours University, France</footnote>

<footnote><sup>c</sup> Inserm U1327 ISCHEMIA, Tours University, France</footnote>

<footnote><sup>d</sup> Bacteriology-Virology-Hygiene Service, CHU Tours, France</footnote>

<footnote><sup>e</sup> ISP UMR1282 INRAE, Tours University, France</footnote>

<footnote><sup>f</sup> Medicine Faculty, Tours University, France</footnote>

<footnote><sup>g</sup> Orthopaedic and Traumatology Surgery Service, CHU Tours, France</footnote>

<footnote><sup>i</sup> Inserm U1069 N2C, Tours University, France</footnote>

<footnote><sup>h</sup> Tropical and Infectious Disease Service, CHU Tours, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: v.tuloup@chu-tours.fr (V. Tuloup).</footnote>
Bone and joint infections (BJI) encompass infections of native bones or joints, prosthetic arthroplasties, and foreign device infections [6]. These conditions require a specialized multidisciplinary approach, combining orthopedic surgery with prolonged antibiotic therapy. Some antibiotics necessitate higher dosages than those typically used for common infections [7]. As a possible result, pharmacological management is frequently associated with a high incidence of adverse events, drug-drug or drug-disease interactions (DDI/DDSI) [8–10]. Evidence remains limited regarding patients with cirrhosis, as only a few studies have examined its impact following prosthetic hip or knee surgery [11–14]. The extant literature consistently indicates that chronic liver disease is associated with an increased risk of impaired wound healing, septic complications, and prolonged hospital stays. In patients with cirrhosis, prosthetic reimplantation procedures carry a higher risk of recurrence than in non-cirrhotic individuals [11]. Additionally, anæsthesia poses a heightened risk of hypotension, morbidity, and mortality due to altered pharmacokinetics and pharmacodynamics [15,16].

In France, multidisciplinary teams specializing in BJI management are organized in the CRIOAC network (Centre de Référence des Infections Ostéoarticulaires Complexes) [17]. Patients from both private and public healthcare facilities can be referred to a CRIOAC center for specialized consultation and guidance on surgical and medical treatment. This study aimed to analyze our local cohort of cirrhotic patients with BJI in view of identifying the needs and challenges specific to this subpopulation.

Our findings should provide valuable insights for clinicians and pharmacists, whatever their experience with BJI treatment, by outlining the unique characteristics and key monitoring considerations for cirrhotic patients with prosthetic or bone-related infections.

## 2. Material and methods

This observational monocentric study analyzed routine care data from January 2013 to December 2023. All patient cases presented at the Tours CRIOAC multidisciplinary meeting (hereafter referred to as “the meeting”) for BJI treatment advice were systematically recorded in the local electronic database linked to the national registry [18]. Patients were screened in this local database for comorbidities using the terms “cirrhosis,” “hepatitis,” and “hepatopathy.” Socio-demographic, biological, and routine clinical care data were collected, including BJI type (infection site, native bone vs. prosthesis), causative pathogens, initial intravenous (IV) therapy, and the oral antibiotic therapy used for step-down treatment. Missing clinical or biological data were retrieved from the hospital’s nominative electronic medical records, as were on BJI eradication at two years post-meeting. Patients hospitalized in peripheral hospitals that did not share data were excluded due to insufficient information.

BJI remission was defined as the absence of patient-reported symptoms, wound inflammation, wound dehiscence, or febrile/subfebrile states at the one-year orthopedic follow-up visit, corroborated by biological test results. A second assessment at two years was performed to detect long-term subclinical infection recurrence. Persistent infection was defined as identification of the same microbial agent following surgical and pharmacological treatment. Recurrence was defined as detection of a different microbial agent in bacteriological tests—with or without the initial causative agent—after previously successful surgical and medical treatment.

Cirrhosis decompensation was defined as unplanned hospitalization in the hepato-gastroenterology department occurring concurrently with infection or within three months post-remission, presenting with hepatic encephalopathy, spontaneous bacterial peritonitis caused by the same pathogen, hepatorenal syndrome, or any condition leading to deterioration in the Child-Turcotte-Pugh (CTP) classification. Adverse events were documented in patient files and consultation reports according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. All-cause mortality was also recorded.

The antimicrobial agents used for BJI treatment were documented,

including their dosages and durations. DDIs and required dosage adjustments due to cirrhosis-related pharmacokinetic alterations were assessed based on electronic prescriptions at the time of the meeting. DDIs and DDSIs were classified as minor if the predicted drug exposure variation (AUC ratio) ranged from 0.75 to 1.5 (where an AUC ratio of 1 indicates no change), moderate if within 0.5–2, and major if outside this range [3]. Predicted AUC ratios were derived using the DDI-Predictor website, the DDI and Cirrhosis web tool and, when necessary, published population pharmacokinetic studies [19]. All statistical analyses were univariate due to the small sample size. Two-sided statistical tests were performed using R software (R Core Team, 2020) and the tidyverse package. This study was approved by the local ethics committee (reference no. 2024_067) and registered in the CNIL database (reference no. 2024_121).

## 3. Results

From January 2013 to February 2023, 18 cirrhotic patients were identified in the CRIOAC meeting database, representing a total of 28 case discussions out of 7050 recorded since the database inception. The number of discussions per patient ranged from one to four within a two-month period.

Patients were predominantly male (11/18; 61.1 %), with a mean age of 68 ± 9.8 years (range: 46–87 years). At the time of the first meeting, CTP classification was predominantly class B (61 %), followed by class A (22 %) and class C (5.5 %; one patient). Two patients could not be classified, as their records were submitted by an external hospital without sufficient information. Population characteristics and liver disease etiology are summarized in Table 1. Bone and joint infections (BJIs) were primarily prosthetic infections (10/18; 61 %), most commonly involving the hip joint (8/18; 44 %). The distribution of anatomical locations and etiologies is illustrated in Fig. 1.

Twenty-three different pathogens were identified in the perioperative samples or fluid collections obtained via aspiration. The most frequently isolated bacteria were staphylococci, accounting for 12 isolates in 10 patients (55 %), including three methicillin-resistant strains.

<table><caption>**Table 1**
Demographic, clinical and biological data of cirrhosis BJI population.</caption><thead><tr><th>Variables</th><th>Value</th></tr></thead><tbody><tr><td>Age, median years (range)</td><td>69 [47–86]</td></tr><tr><td>Male gender (%)</td><td>11 (61.1)</td></tr><tr><td>Etiology of liver disease</td><td></td></tr><tr><td>Alcohol</td><td>10 (55.5)</td></tr><tr><td>Combined</td><td>3 (16.7)</td></tr><tr><td>NASH</td><td>1 (5.5)</td></tr><tr><td>Viral hepatitis</td><td>2 (11.1)</td></tr><tr><td>NR</td><td>2 (11.1)</td></tr><tr><td>CTP class at the infection time</td><td></td></tr><tr><td>A</td><td>4 (22.2)</td></tr><tr><td>B</td><td>11 (61.1)</td></tr><tr><td>C</td><td>1 (5.5)</td></tr><tr><td>NR</td><td>2 (11.1)</td></tr><tr><td>Ascites</td><td></td></tr><tr><td>presence</td><td>6 (33.3)</td></tr><tr><td>absence</td><td>8 (44.4)</td></tr><tr><td>NR</td><td>4 (22.2)</td></tr><tr><td>Esophageal varices</td><td></td></tr><tr><td>presence</td><td>5 (27.7)</td></tr><tr><td>absence</td><td>9 (50)</td></tr><tr><td>NR</td><td>4 (22.2)</td></tr><tr><td>V factor (%)</td><td>66 +/− 14 %</td></tr><tr><td>Prothrombin Time (%)</td><td>64 +/− 13 %</td></tr><tr><td>Albumin</td><td>27 +/− 6 g/L</td></tr><tr><td>Seric Creatinine</td><td>60 +/− 48 µmol/L</td></tr><tr><td>CKD-EPI clearance estimation</td><td>87 +/− 47 mL/min</td></tr><tr><td>C-reactive protein</td><td>59 +/− 52 mg/L</td></tr><tr><td>Weight</td><td>69 +/− 20 kg</td></tr><tr><td>BMI</td><td>24 +/− 7 kg/m<sup>2</sup></td></tr></tbody></table>

NASH: non-alcoholic steatohepatitis; NR: not specified; BMI: Body Mass Index.
<figure><img src="image_2.png" /><figcaption>Fig. 1. Heatmap representation of bone and joint infection etiology regarding anatomic localization.</figcaption></figure>

Gram-negative bacilli were identified in six isolates from five patients (28 %). Other identified Gram-positive pathogens included *Streptococcus dysgalactiae*, *Corynebacterium striatum*, and *Cutibacterium acnes*. None of these bacteria were classified as contaminants, as multiple positive cultures confirmed their clinical relevance. Cultures were sterile in two patients (11 %). The full distribution is presented in Table 2.

Polymicrobial infections were observed in four patients (22 %), with one patient harboring three distinct pathogens (methicillin-resistant *Staphylococcus epidermidis*, *Staphylococcus lugdunensis*, and *Serratia marcescens*). This patient was a 70-year-old male, CTP class B, with chronic renal impairment and type 2 diabetes, presenting with a chronic prosthetic joint infection (PJI) six months after total knee arthroplasty. Three other patients had dual-pathogen infections: a CTP class B male with a history of hematogenous infection due to *Salmonella enteritidis* and *Enterobacter aerogenes* affecting a total hip prosthesis; a 51-year-old CTP class B male with a history of native knee arthritis, infected with methicillin-sensitive *Staphylococcus aureus* and *Corynebacterium striatum*; a 66-year-old CTP class A female with a history of breast cancer. One month after total hip arthroplasty, she developed a draining fistula, and deep tissue cultures grew *Streptococcus dysgalactiae* and *Serratia marcescens*.

All other patients had monomicrobial infections. Two patients had non-contributory cultures due to prior antibiotic use; however, their clinical presentation was unequivocal, with clear signs of deep infection and osteitis markers on imaging. These patients received empirical broad-spectrum antibiotic therapy and were closely monitored during follow-up. Neither experienced relapse.

This cohort was compared to a previously published BJI patient

cohort from the same center (data not shown) after excluding three patients with liver disease [20]. No statistically significant differences were observed between 18 cirrhotic patients and 126 non-cirrhotic patients regarding staphylococcal infections (p = 0.615), methicillin-resistant bacteria (p = 0.109), Gram-negative bacilli (p = 0.689), negative cultures (p = 0.742) or polymicrobial infections (p = 0.353).

Out of the 18 patient cases presented at the multidisciplinary meeting, 16 underwent surgery. Two patients were deemed ineligible for surgery due to excessive perioperative mortality risk, considering their age, cirrhosis severity, and comorbidities. The proposed management for one of these patients was maintenance of a productive fistula, while the second received suppressive antibiotic therapy (SAT). Among the 16 remaining patients, the choice of surgical approach was guided by infection chronicity: 11 experienced an acute BJI (lasting fewer than four weeks from initial surgery or symptoms) and were operated by debridement (for osteitis/arthritis) or DAIR (debridement, antibiotics, and implant retention). Five patients had chronic infections (lasting more than four weeks), and required prosthetic replacement as the standard approach. Among them, four underwent a two-stage revision due to their comorbidities, while one underwent a one-stage revision.

Six out of these 16 patients (37 %) experienced relapse. Among them, four patients (66 %) did not undergo further surgery due to their clinical condition (three agreed to maintain a productive fistula, one received SAT), two patients (33 %) underwent surgical intervention (one DAIR and one hip excision arthroplasty). Two out of the six patients relapsed again (33 %), both of them requiring excision arthroplasty. One patient experienced an additional relapse, leading to a final decision to maintain a productive fistula. This patient was a 69-year-old male, CTP class B, with a history of heart failure and type 2 diabetes.

The full sequence of surgical interventions for each patient is illustrated in Fig. 2.

Probabilistic antibiotic therapy, initiated immediately post-surgery, consisted of piperacillin-tazobactam combined with either vancomycin or linezolid, in accordance with institutional guidelines. One patient received aztreonam and daptomycin due to a documented allergy to beta-lactams and extensive prior use of linezolid, respectively. Probabilistic therapy was subsequently tailored to the identified pathogens and their antibiograms between days 6 and 14. Sixteen patients received first-line adapted antibiotic therapy, while one patient developed a fistula and did not require antibiotics, and another patient died from complications of cirrhosis before therapy adaptation. The majority of antibiotic regimens were oral monotherapies (9/16; 56.2 %), followed by combined oral therapies (6/16; 37.5 %). One patient (6.25 %) received intravenous therapy for six weeks due to swallowing

<table><caption>**Table 2**
Microorganism distribution in our population.</caption><thead><tr><th>Microorganisms found</th><th>Value</th><th>Percentages of pathogens</th></tr></thead><tbody><tr><td><i>Staphylococcus aureus</i>, methicillin-sensitive</td><td>4</td><td>17 %</td></tr><tr><td><i>Staphylococcus aureus</i>, methicillin-resistant</td><td>2</td><td>9 %</td></tr><tr><td><i>Staphylococcus epidermidis</i>, methicillin-sensitive</td><td>2</td><td>9 %</td></tr><tr><td><i>Staphylococcus epidermidis</i>, methicillin-resistant</td><td>1</td><td>4 %</td></tr><tr><td>Coagulase-negative staphylococci</td><td>3</td><td>13 %</td></tr><tr><td>Streptococcus dysgalactiae</td><td>1</td><td>4 %</td></tr><tr><td>Corynebacterium spp</td><td>1</td><td>4 %</td></tr><tr><td>Cutibacterium acnes</td><td>1</td><td>4 %</td></tr><tr><td>Gram-negative bacilli</td><td>6</td><td>26 %</td></tr><tr><td>including Serratia marcescens</td><td>3</td><td>13 %</td></tr><tr><td>Non contributory culture</td><td>2</td><td>9 %</td></tr></tbody></table>
<figure><img src="image_3.png" /><figcaption>Fig. 2. Sequential treatment advice for each patient. DAIR: debridement, antibiotics, implant retention. SAT: suppressive antibiotic therapy. w/o: without.</figcaption></figure>

difficulties. Fourteen treatments (14/16; 87.5 %) were prescribed for six weeks post-surgery, one for three months, and one as SAT for an indefinite duration.

Fluoroquinolones were the most frequently prescribed class (7/22 prescriptions; 31.8 %), primarily in combination (4/7; 57 %), followed by clindamycin (4/22; 18.2 %), which was equally prescribed as monotherapy and in combination. Rifampicin was prescribed to three patients (3/22; 13.6 %), always in combination. Trimethoprim-sulfamethoxazole was also prescribed to three patients, with two of these in combination. Other prescribed drugs included amoxicillin and doxycycline (both 2/22; 9.1 % each), and daptomycin. A detailed overview of each antibiotic therapy, including dosage and duration, is

<table><caption>**Table 3**
Prescriptions overview.</caption><thead><tr><th>patient ID</th><th>Antibiotic prescription</th><th>Prescription length</th><th>CTP class</th></tr></thead><tbody><tr><td>1</td><td>Rifampicin 600 mg + levofloxacin 500 mg</td><td>3 M</td><td>B</td></tr><tr><td>2</td><td>Amoxicillin 2 g t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>3</td><td>Clindamycin 600 mg t.i.d + SMX-TMP 160/800 mg b.i.d</td><td>6 W</td><td>A</td></tr><tr><td>4</td><td>Clindamycin 600 mg t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>5</td><td>Daptomycin 10 mg/kg</td><td>6 W</td><td>C</td></tr><tr><td>6</td><td>SMX-TMP 160/800 mg b.i.d</td><td>6 W</td><td>A</td></tr><tr><td>7</td><td>Clindamycin 600 mg b.i.d</td><td>SAT</td><td>B</td></tr><tr><td>8</td><td>Ciprofloxacin 750 mg + SMX-TMP 160/800 mg b.i.d</td><td>6 W</td><td>B</td></tr><tr><td>9</td><td>Amoxicillin 2 g t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>10</td><td>Ciprofloxacin 750 mg b.i.d</td><td>6 W</td><td>B</td></tr><tr><td>11</td><td>Clindamycin 300 mg t.i.d – ofloxacin 200 mg t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>12</td><td>Rifampicin 600 mg b.i.d – ofloxacin 200 mg t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>13</td><td>Rifampicin 600 mg b.i.d – ofloxacin 200 mg t.i.d</td><td>6 W</td><td>B</td></tr><tr><td>14</td><td>Ciprofloxacin 750 mg b.i.d</td><td>6 W</td><td>A</td></tr><tr><td>15</td><td>Doxycycline 200 mg</td><td>6 W</td><td>B</td></tr><tr><td>16</td><td>Doxycycline 200 mg</td><td>6 W</td><td>B</td></tr></tbody></table>

t.i.d: three times a day; b.i.d: twice a day. SMX-TMP: trimethoprim – sulfamethoxazole; W: week. M: months. CTP: Child-Turcotte-Pugh classification.

provided in Table 3.

For each antibiotic prescribed in our study population, we reviewed the literature regarding dosage adjustments required for cirrhotic patients.

Penicillin and its derivatives are minimally metabolized by the liver and generally do not require systematic dose adjustments. However, some drugs necessitate optimization based on the stage of cirrhosis. Hepatorenal syndrome or acute kidney injury concomitant with cirrhosis may lead to overexposure of penicillin, in which case a dose reduction is suggested for amoxicillin, nafcillin, or ampicillin [21–25]. Although there are limited studies on piperacillin (none with the beta-lactamase inhibitor tazobactam), dose adjustments may not be necessary outside of hepatorenal syndrome, notwithstanding the increased half-life of piperacillin in cirrhotic patients due to ascites forming a retention compartment [26].

Quinolones are widely used in patients with cirrhosis, particularly for spontaneous bacterial peritonitis (SBP). Most drugs in this class do not require dose adjustment in mild to moderate cirrhosis, as they are not extensively metabolized [22]. However, studies on ofloxacin suggest a 50 % dose reduction (maximum 400 mg per day) in severe cirrhosis [27,28]. Ciprofloxacin dosage may also need to be adjusted in severe cirrhosis, although no precise recommendations exist, similar to pefloxacin [29–32]. For all fluoroquinolones, therapeutic drug monitoring (TDM) is recommended in CTP class C patients [33].

For *Staphylococcus aureus* infections, the combination of a quinolone with rifampicin is considered the gold standard. Since rifampicin is partially metabolized in the liver, its plasma concentration is expected to increase in cirrhotic patients. Pharmacokinetic modelling and TDM suggest reducing the dose to 8 mg/kg/day to achieve trough concentrations equivalent to those observed with 10–12 mg/kg/day in non-cirrhotic patients [22,34,35]. As a second-line treatment, clindamycin (a lincosamide) may be considered. Three studies were identified, though only one investigated repeated administration. Due to its almost exclusive metabolism via cytochrome P450 3A4, clindamycin is expected to accumulate in severe cirrhosis. A 50 % dose reduction should be considered, with regular monitoring of liver function [10,36,37]. Although the free fraction excreted is higher in cirrhotic patients, a greater dose reduction does not appear necessary, despite the potential
impact on hepatic metabolism [3].

Linezolid, which is often used in combination with piperacillin-
tazobactam as probabilistic antibiotic therapy, is a relatively novel
antibiotic. Studies have highlighted an increased number of adverse
events in cirrhotic patients when linezolid is administered at standard
doses. Authors recommend reducing the dose to 300 mg twice daily or
600 mg per day, in addition to therapeutic drug monitoring for pro-
longed treatments [38,39].

In cases of beta-lactam allergy, aztreonam may be used. Increased clearance is expected in the event of hepatic insufficiency, but moderate renal insufficiency can mitigate this difference [40]. Macleod et al. proposed dose reduction specifically for alcoholic cirrhosis in long-term treatment carried out due to specific accumulation [41]. Similarly, meropenem should be considered for penicillin-resistant infections before transitioning to oral therapy. Studies indicate that due to a large therapeutic margin, cirrhosis has minimal impact in CTP class A or B [42]. However, meropenem should be initiated cautiously in CTP class C, especially with concomitant acute kidney disease, which increases the risk of overexposure. In cases of ascites, a loading dose is recommended to achieve therapeutic trough concentrations in serum [43,44].

Doxycycline, a tetracycline drug, is well-absorbed and exhibits favorable bone concentration [45]. However, our literature review did not identify any pharmacokinetic data or dosing recommendations for doxycycline in patients with hepatic impairment. Hepatic monitoring is essential during treatment, and potential hepatotoxicity warrants caution before initiating therapy in patients with decompensated cirrhosis.

While trimethoprim-sulfamethoxazole (TMP-SMX) is partially elim-
inated by the liver, it is generally well-tolerated and commonly used for
ascites infections without requiring initial dose adjustments. Close
clinical and pharmacological monitoring is recommended. Similarly,
vancomycin and daptomycin can be prescribed at standard doses for
patients with healthy livers, with usual supervision, except in cases of
concomitant hepatorenal syndrome [21,22,44,46].

Only two out of seven patients required dose adjustments. No antibiotic-related side effects were reported in the electronic consultation files, regardless of dose adaptation. Six patients died during follow-up, constituting 33.3 % of the cohort. None of the deaths were attributed to BJI. Two patients died from complications of cirrhosis, two from pulmonary cancer, one from hepatocellular carcinoma, and one from cardiac decompensation associated with acute kidney injury. These findings align with the overall BJI population, in which mortality rates are approximately 21 % at five years post-prosthetic joint infection (PJI) and rise to 45 % at ten years [47,48].

4. Discussion

Few research teams have focused on BJIs in cirrhotic patients, as this
group is not the primary population affected. Most studies have
concentrated on prosthetic-related infections and have not described
native bone infections. Our cohort study indicates that this population
may require specific attention during clinical evaluations, particularly in
cases of moderate or severe cirrhosis. Although BJIs in these patients are
typically monobacterial, and progression-free survival at one- and two-
years post-surgery is comparable to that of non-cirrhotic patients,
careful management is essential.

The greatest challenge in managing BJIs in cirrhotic patients is the
presence of comorbidities and polypharmacy associated with cirrhosis.
Pathophysiological aspects of cirrhosis, such as immunosuppression,
decreased metabolism due to inflammation, and hepatorenal syndrome,
significantly contribute to overall body decompensation and, conse-
quently, BJI treatment failure. Introducing a new drug to a cirrhotic
patient's regimen poses a risk of DDIs or DDIs and must be considered a
potential factor for hepatic decompensation [12]. Although our study
did not demonstrate a difference in treatment failure rates compared to
the general population, the majority of patients in CTP class C should be

monitored more closely due to significant hemodynamic and pharma-
cokinetic variations related to the decompensation of liver disease.

The impact of cirrhosis on the pharmacokinetics of antimicrobial treatments remains underexplored, with inconsistent recommendations that often diverge from the Summary of Product Characteristics (SPC) of the relevant drugs. Dafonte et al. reviewed 706 clinically applicable recommendations for 316 molecules, finding that only 22 drugs had consistent recommendations, of which only six aligned with their respective SPCs [4]. As a result, dosage adjustments for treatments initiated during CRIOAC meetings should be approached with great caution. Despite the limited bibliographic data available to clinicians, it remains crucial to administer long-term (at least six weeks) and often high-dose antibiotic therapy while minimizing adverse effects—affecting 60 % of patients—and avoiding underexposure, which could lead to recurrence or antimicrobial resistance [49,50]. This challenge is particularly pronounced in patients with severe cirrhosis (CTP class C), especially those who have undergone transjugal intrahepatic portosystemic shunt (TIPS) placement or suffer from esophageal varices. These different conditions alter intrinsic hepatic clearance and drug absorption, potentially increasing toxicity due to overexposure. However, interindividual variability remains high, and a lack of dedicated studies makes accurate predictions difficult to render [51–54].

In our study, cirrhotic patients at risk of drug-disease interactions did not report major adverse effects necessitating treatment modifications. However, given the small sample size, these findings cannot be generalized to the broader population of cirrhotic patients with BJIs. Prospective studies incorporating TDM in a larger cohort are necessary to refine dosing strategies for this population. Furthermore, due to the retrospective nature of our study, we relied on hospital records and consultation reports, which are known to be insufficiently sensitive in detection of adverse events. Consequently, a significant number of mild to moderate adverse effects may have gone unreported [55–57].

This study has several limitations. First, the small sample size limits the robustness of our conclusions. Additionally, some patients could not be included due to their being managed in external centers without accessible electronic health records. As regards patients discussed during the early years of follow-up, missing data could not be retrieved, precluding their inclusion. The high prevalence of handwritten prescriptions during those early years further hindered our attempts to assess drug interactions between patients' pre-existing treatments and the antibiotics administered. To address these gaps, a prospective follow-up study is planned. Similarly, a small proportion of cultures were sterile. However, we were unable to determine whether sterility resulted from the absence of infection or from prior antibiotic use—particularly quinolones for ascitic fluid infection prophylaxis—as external centers did not provide records of previous prescriptions at the time of the meeting.

As our results indicate, none of the patients in our cohort died from BJI or required amputation surgery, which is consistent with outcomes in the general BJI patient population. The most significant challenges in managing cirrhotic patients remain pharmacological optimization, particularly in severe cirrhosis, due to a lack of clear dosing recommendations, and impaired wound healing. Optimal care for cirrhotic patients requires a multidisciplinary approach with expertise in managing hepatic decompensation, whether triggered by infection or by the antimicrobial agents used for treatment. The literature consistently proposes multidisciplinary management of BJI patients, and we advocate for this approach, particularly for those with CTP class B or C cirrhosis, the objective being to minimize the risk of DDIs-DDSIs and rehospitalization [58,59].

5. Conclusion

This observational study presents promising results regarding management of this subpopulation of patients, both surgically and microbiologically. The main challenge in treating these patients lies in
balancing antimicrobial therapy, multiple surgical interventions, and the risk of hepatic decompensation. Multidisciplinary monitoring is essential to ensure optimal patient care. We recommend dose adjustments for antimicrobial treatments, particularly from CTP class B onwards, due to an increased risk of cirrhotic decompensation, which can lead to drug accumulation and exacerbated adverse effects, potentially resulting in treatment failure. However, for patients classified as CTP class A, close monitoring and consistent collaboration with the referring hepatologist may be sufficient to ensure safe and effective treatment.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors, and was performed as part of routine CRIOAC activity.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgements

We would like to thank all the CRIOAC participants who contributed to the production of this article, particular I. LAPLAIGE for her secretarial expertise and data collection assistance.

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