Histological analysis of the medial gastrocnemius muscle in young healthy children.

Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking. Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children. Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2-10 years subdivided into 4 age groups (2-4, 4-6, 6-8 and 8-10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability. Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls. Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.

Advanced imaging shows extra-articular abscesses in two out of three adult patients with septic arthritis of the native hip joint.

Background: Septic arthritis (SA) of the native adult hip is a rare orthopaedic emergency requiring prompt diagnosis and treatment. As clinical presentation and laboratory findings are frequently atypical, advanced imaging is often requested. This retrospective study aimed to investigate the prevalence and pattern of extra-articular infectious manifestations and their implications for pre-operative advanced imaging in patients with proven SA of the native hip joint. Methods: Out of 41 patients treated surgically for SA of the native hip during a 16-year period at our tertiary referral hospital, 25 received advanced imaging (computed tomography (CT), magnetic resonance imaging (MRI), or fluorodeoxyglucose positron emission tomography (FDG PET-CT)) prior to initial intervention. For each investigation, a specific set of variables was systematically interpreted, and the most suitable surgical approach was determined. The prognostic value was evaluated by comparing specific outcome measures and the extent of extra-articular involvement. Results: It was found that 32 % of patients had an abscess in one anatomical region, 32 % of patients had abscesses in multiple anatomical regions, and only 36 % of patients had no substantial abscess. Gluteal abscesses were especially common in patients with SA due to contiguous spread. Abscesses in the iliopsoas region were more common in patients with SA due to hematogenous seeding. A combination of several different surgical approaches was deemed necessary to adequately deal with the various presentations. No significant prognostic factors could be identified. Conclusion: We recommend performing advanced imaging in patients with suspected or proven septic arthritis of the native hip joint, as extra-articular abscesses are present in 64 % and might require varying anatomical approaches.

The surgical management of fracture-related infection. Surgical strategy selection and the need for early surgical intervention.

The aim of this narrative review is to describe the various surgical management strategies employed in fracture-related infection (FRI), to explore how they are selected and discuss the rationale for early surgical intervention. Surgical treatment options in patients with FRI include debridement, antibiotics and implant retention (DAIR), revision (exchange) or removal. In selecting a treatment strategy, a variety of factors need to be considered, including the condition of the bone, soft tissues, host and causative microorganism. Irrespective of the selected treatment strategy, prompt surgical intervention should be considered in order to confirm the diagnosis of an FRI, to identify the causative organism, remove necrotic or non-viable tissue that can serve as a nidus for ongoing infection, ensure a healthy soft tissue envelope and to prevent the vicious cycle of infection associated with skeletal and/or implant instability. Ultimately, the objective is to prevent the establishment of a persistent infection. Urgent surgery may be indicated in case of active, progressive disease with systemic deterioration, local progression of infection, deterioration of soft tissues, or progressive fracture instability. In case of static disease, the patient should be monitored closely and surgery can be performed on an elective basis, allowing adequate time for optimisation of the host through risk factor modification, optimisation of the soft tissues and careful planning of the surgery.

Diagnostic Performance of a telephone questionnaire for fracture-related infections (FRIs) in open tibia fracture patients in Tanzania.

INTRODUCTION: Fracture-related infections (FRIs) are a major cause of trauma-associated morbidity worldwide. In 2018, an expert group supported by the AO Foundation, European Bone and Joint Infection Society developed a consensus definition of FRI. Still, there is limited knowledge on the applicability of this definition in low- and middle-income countries (LMICs). Given the unique barriers that cause low follow-up rates for orthopaedic trauma patients in LMICs, this study aims to evaluate the diagnostic performance of a telephone questionnaire in identifying patients with FRIs after open tibia fracture fixation in Tanzania. MATERIALS AND METHODS: Patients from a randomized controlled trial investigating the infection prevention benefit of locally applied gentamycin for open tibial fractures were included. Patients completed FRI based telephone questionnaires 7-10 days prior to scheduled follow-ups at 6 weeks, 3 months, 6 months, 9 months, and 1 year. The questionnaire included two "confirmatory" criteria questions for FRI (i.e., open wound and purulent drainage) and three "suggestive" criteria questions (i.e., wound drainage, fever, and warmth). Contingency tests were performed to identify the sensitivity and specificity between answers and adjudicated FRI diagnoses at the corresponding in-person follow-up. Data was analysed using STATA version 15.0 and MedCalc's online diagnostic test calculator. RESULTS: There were a total of 234 complete questionnaires and 85 unique patients included. The sensitivity and specificity of having any positive answer in the questionnaire was highest at 6 months (100 % and 92.5 %, respectively). For all time-points pooled, sensitivity was 71.4 % and specificity was 93.0 %. Drainage had the highest sensitivity (71.4 %) while fever had the highest specificity (99.6 %). For confirmatory criteria, sensitivity was 14.3 % and specificity was 96.0 %. Contrastingly, the sensitivity for suggestive criteria was higher (71.4 %), with a similar specificity (93.8 %). CONCLUSION: Our study indicates that telephone questionnaires have adequate diagnostic performance when assessing FRIs. The presence of drainage identified the majority of patients with FRI, and specificities were high across confirmatory and suggestive criteria. Our study is one of the first to evaluate telephone questionnaires as a diagnostic tool for FRIs in patients with open tibia fractures in a LMIC hospital and validates the FRI consensus definition criteria.

Key aspects of soft tissue management in fracture-related infection: recommendations from an international expert group.

A judicious, well-planned bone and soft tissue debridement remains one of the cornerstones of state-of-the-art treatment of fracture-related infection (FRI). Meticulous surgical excision of all non-viable tissue can, however, lead to the creation of large soft tissue defects. The management of these defects is complex and numerous factors need to be considered when selecting the most appropriate approach. This narrative review summarizes the current evidence with respect to soft tissue management in patients diagnosed with FRI. Specifically we discuss the optimal timing for tissue closure following debridement in cases of FRI, the need for negative microbiological culture results from the surgical site as a prerequisite for definitive wound closure, the optimal type of flap in case of large soft tissue defects caused by FRI and the role of negative pressure wound therapy (NPWT) in FRI. Finally, recommendations are made with regard to soft tissue management in FRI that should be useful for clinicians in daily clinical practice.Level of evidence Level V.

The global burden of fracture-related infection: can we do better?

Fracture-related infection is a major complication related to musculoskeletal injuries that not only has important clinical consequences, but also a substantial socioeconomic impact. Although fracture-related infection is one of the oldest disease entities known to mankind, it has only recently been defined and, therefore, its global burden is still largely unknown. In this Personal View, we describe the origin of the term fracture-related infection, present the available data on its global impact, and discuss important aspects regarding its prevention and management that could lead to improved outcomes in both high-resource and low-resource settings. We also highlight the need for health-care systems to be adequately compensated for the high cost of human resources (trained staff) and well-equipped facilities required to adequately care for these complex patients. Our aim is to increase awareness among clinicians and policy makers that fracture-related infection is a disease entity that deserves prioritisation in terms of research, with the goal to standardise treatment and improve patient outcomes on a global scale.

Should treatment decisions in septic arthritis of the native hip joint be based on the route of infection?

Background: Surgical management of septic arthritis (SA) of the hip aims at treating the infection by either preserving, resecting or replacing the joint. In some cases, joint preservation should be attempted, whereas other cases would benefit from immediate joint resection or replacement. Prognostic factors have been proposed to guide decision-making. We hypothesized that most of these factors can be simplified to three subgroups based on the route of infection: contiguous spreading, direct inoculation or hematogenous seeding. Methods: A total of 41 patients have been treated surgically for SA of the native hip at our tertiary hospital during the last 16 years. Medical records were studied, and various patient and disease characteristics were collated. Results: Significant differences between (1) level of fitness, (2) condition of the hip joint, (3) micro-organisms and (4) chance of femoral head preservation were found for patients with SA of the native hip resulting from the three aforementioned subgroups. Femoral head resection was necessary at one point in 85 % of patients. Patients with hematogenous infections of undamaged hips had a reasonable chance (53 %) of avoiding joint resection or replacement. Hip arthroplasty was performed on 46.3 % of patients, with an infection rate of 10.5 %. Conclusion: Patients with SA of the native hip resulting from contiguous spreading, hematogenous seeding or direct inoculation differ significantly and should be considered distinct clinical entities. Route of infection is directly related to the chance of femoral head preservation and should, therefore, guide decision-making. Only patients with hematogenous infection to a previously healthy hip had the possibility of femoral head preservation.

Bedside check of medication appropriateness (BED-CMA) as a risk-based tool for bedside clinical pharmacy services: A proof-of-concept study at the trauma surgery ward.

Background: Bedside clinical pharmacy prevents drug-related problems, but is not feasible in many countries due to limited resources. Hence, clinical rules using structural information in the electronic health record can help identifying potentially inappropriate prescriptions (PIPs). We aimed to develop and implement a risk-based clinical pharmacy service and evaluate its impact on prescribing at the trauma surgery ward. Methods: The proportion of residual PIPs per day, i.e. the number of PIPs that persisted up to 24 h after pharmacist intervention divided by the number of PIPs at T0, was evaluated before and after implementation of the intervention in an interrupted time series analysis. The pre-intervention cohort received usual pharmacy services, i.e. a 0.3 FTE clinical pharmacist trainee. Fifteen clinical rules, targeting antimicrobial, anticoagulant and analgesic therapy were implemented in the post-intervention period. The pre-intervention period was compared to two post-intervention scenarios: A) clinical rule alerts reviewed by a 0.3 FTE clinical pharmacist trainee; and B) clinical rule alerts reviewed daily for approximately 1 h by a clinical pharmacist trainee. Results: Pre-intervention, a median proportion of 67% (range 0%-100%) residual PIPs per day was observed. Scenario A showed an immediate relative reduction of 14% (p = 0.72) and scenario B a significant immediate relative reduction of 85% (p = 0.0015) in residual PIPs per day. In scenario A, recommendations were provided for 19% of clinical rule alerts, of which 67% was accepted by the surgeon within 24 h. In scenario B, recommendations were given for 56% of alerts, of which 84% was accepted. Conclusions: Using clinical rules is an effective approach to organize bedside clinical pharmacy services and improves prescribing at the trauma surgery ward. Advanced training and daily follow-up of the clinical rules are two requirements to be considered.

Alginate microbeads and hydrogels delivering meropenem and bacteriophages to treat Pseudomonas aeruginosa fracture-related infections.

Bacteriophage (phage) therapy has shown promise in treating fracture-related infection (FRI); however, questions remain regarding phage efficacy against biofilms, phage-antibiotic interaction, administration routes and dosing, and the development of phage resistance. The goal of this study was to develop a dual antibiotic-phage delivery system containing hydrogel and alginate microbeads loaded with a phage cocktail plus meropenem and evaluate efficacy against muti-drug resistant Pseudomonas aeruginosa. Two phages (FJK.R9-30 and MK.R3-15) displayed enhanced antibiotic activity against P. aeruginosa biofilms when tested in combination with meropenem. The antimicrobial activity of both antibiotic and phage was retained for eight days at 37 °C in dual phage and antibiotic loaded hydrogel with microbeads (PA-HM). In a mouse FRI model, phages were recovered from all tissues within all treatment groups receiving dual PA-HM. Moreover, animals that received the dual PA-HM either with or without systemic antibiotics had less incidence of phage resistance and less serum neutralization compared to phages in saline. The dual PA-HM could reduce bacterial load in soft tissue when combined with systemic antibiotics, although the infection was not eradicated. The use of alginate microbeads and injectable hydrogel for controlled release of phages and antibiotics, leads to the reduced development of phage resistance and lower exposure to the adaptive immune system, which highlights the translational potential of the dual PA-HM. However, further optimization of phage therapy and its delivery system is necessary to achieve higher bacterial killing activity in vivo in the future.

Stability of magistral phage preparations before therapeutic application in patients with chronic rhinosinusitis, sepsis, pulmonary, and musculoskeletal infections.

IMPORTANCE: As antimicrobial resistance becomes more prevalent, the application of (bacterio)phage therapy as an alternative treatment for difficult-to-treat infections is (re)gaining popularity. Over the past decade, numerous promising case reports and series have been published demonstrating the therapeutic potential of phage therapy. However, important questions remain regarding the optimal treatment protocol and, unlike for medicinal products, there are currently no predefined quality standards for the stability of phage preparations. Phage titers can be influenced by several factors which could lead to reduced titers after preparation and storage and, ultimately, subtherapeutic applications. Determining the stability of different phages in different recipients according to the route of administration is therefore one of the first important steps in establishing a standardized protocol for phage therapy.

Treatment and outcome of fracture-related infection of the clavicle.

INTRODUCTION: The number of operatively treated clavicle fractures has increased over the past decades. Consequently, this has led to an increase in secondary procedures required to treat complications such as fracture-related infection (FRI). The primary objective of this study was to assess the clinical and functional outcome of patients treated for FRI of the clavicle. The secondary objectives were to evaluate the healthcare costs and propose a standardized protocol for the surgical management of this complication. METHODS: All patients with a clavicle fracture who underwent open reduction and internal fixation (ORIF) between 1 January 2015 and 1 March 2022 were retrospectively evaluated. This study included patients with an FRI who were diagnosed and treated according to the recommendations of a multidisciplinary team at the University Hospitals Leuven, Belgium. RESULTS: We evaluated 626 patients with 630 clavicle fractures who underwent ORIF. In total, 28 patients were diagnosed with an FRI. Of these, eight (29%) underwent definitive implant removal, five (18%) underwent debridement, antimicrobial treatment and implant retention, and fourteen patients (50%) had their implant exchanged in either a single-stage procedure, a two-stage procedure or after multiple revisions. One patient (3.6%) underwent resection of the clavicle. Twelve patients (43%) underwent autologous bone grafting (tricortical iliac crest bone graft (n = 6), free vascularized fibular graft (n = 5), cancellous bone graft (n = 1)) to reconstruct the bone defect. The median follow-up was 32.3 (P25-P75: 23.9-51.1) months. Two patients (7.1%) experienced a recurrence of infection. The functional outcome was satisfactory, with 26 out of 28 patients (93%) having full range of motion. The median healthcare cost was € 11.506 (P25-P75: € 7.953-23.798) per patient. CONCLUSION: FRI is a serious complication that can occur after the surgical treatment of clavicle fractures. In our opinion, when treated adequately using a multidisciplinary patient-specific approach, the outcome of patients with an FRI of the clavicle is good. The median healthcare costs of these patients are up to 3.5 times higher compared to non-infected operatively treated clavicle fractures. Although not studied individually, we consider factors such as the size of the bone defect, condition of the soft tissue, and patient demand important when it comes to guiding our surgical decision making in cases of osseous defects.

Diagnosis of fracture-related infection in patients without clinical confirmatory criteria: an international retrospective cohort study.

Background: fracture-related infection (FRI) remains a serious complication in orthopedic trauma. To standardize daily clinical practice, a consensus definition was established, based on confirmatory and suggestive criteria. In the presence of clinical confirmatory criteria, the diagnosis of an FRI is evident, and treatment can be started. However, if these criteria are absent, the decision to surgically collect deep tissue cultures can only be based on suggestive criteria. The primary study aim was to characterize the subpopulation of FRI patients presenting without clinical confirmatory criteria (fistula, sinus, wound breakdown, purulent wound drainage or presence of pus during surgery). The secondary aims were to describe the prevalence of the diagnostic criteria for FRI and present the microbiological characteristics, both for the entire FRI population. Methods: a multicenter, retrospective cohort study was performed, reporting the demographic, clinical and microbiological characteristics of 609 patients (with 613 fractures) who were treated for FRI based on the recommendations of a multidisciplinary team. Patients were divided in three groups, including the total population and two subgroups of patients presenting with or without clinical confirmatory criteria. Results: clinical and microbiological confirmatory criteria were present in 77 % and 87 % of the included fractures, respectively. Of patients, 23 % presented without clinical confirmatory criteria, and they mostly displayed one (31 %) or two (23 %) suggestive clinical criteria (redness, swelling, warmth, pain, fever, new-onset joint effusion, persisting/increasing/new-onset wound drainage). The prevalence of any suggestive clinical, radiological or laboratory criteria in this subgroup was 85 %, 55 % and 97 %, respectively. Most infections were monomicrobial (64 %) and caused by Staphylococcus aureus. Conclusion: clinical confirmatory criteria were absent in 23 % of the FRIs. In these cases, the decision to operatively collect deep tissue cultures was based on clinical, radiological and laboratory suggestive criteria. The combined use of these criteria should guide physicians in the management pathway of FRI. Further research is needed to provide guidelines on the decision to proceed with surgery when only these suggestive criteria are present.

Characterization of a Bacteriophage GEC_vB_Bfr_UZM3 Active against Bacteroides fragilis.

Bacteroides fragilis is a commensal gut bacterium that is associated with a number of blood and tissue infections. It has not yet been recognized as one of the drug-resistant human pathogens, but cases of the refractory infections, caused by strains that are not susceptible to the common antibiotic regimes established for B. fragilis, have been more frequently reported. Bacteriophages (phages) were found to be a successful antibacterial alternative to antibiotic therapy in many cases of multidrug-resistant (MDR) bacterial infections. We have characterized the bacteriophage GEC_vB_Bfr_UZM3 (UZM3), which was used for the treatment of a patient with a chronic osteomyelitis caused by a B. fragilis mixed infection. Studied biological and morphological properties of UZM3 showed that it seems to represent a strictly lytic phage belonging to a siphovirus morphotype. It is characterized by high stability at body temperature and in pH environments for about 6 h. Whole genome sequencing analysis of the phage UZM3 showed that it does not harbor any known virulence genes and can be considered as a potential therapeutic phage to be used against B. fragilis infections.

Bacteriophage therapy for human musculoskeletal and skin/soft tissue infections.

BACKGROUND: Bacteriophage therapy has a long history in the treatment of musculoskeletal and skin/soft tissue infections, particularly in the former Soviet Union. Due to the global rise in antimicrobial resistance, phage application has experienced a resurgence of interest and expanded to many countries. OBJECTIVES: This narrative review aims to provide clinical microbiologists, infectious disease specialists and surgeons a brief history of bacteriophage therapy for human musculoskeletal and soft tissue infections, as well as data on current practices and ongoing clinical studies. SOURCES: A search of PubMed and Clinicaltrials.gov was performed to identify relevant studies. Search terms were 'bacteriophage therapy', 'musculoskeletal infection' and 'soft tissue infection'. The bibliography of all retrieved articles was checked for additional relevant references. CONTENT: Past and current data on the use of bacteriophage therapy for human musculoskeletal, skin and soft tissue infections are evaluated. Moreover, we present the clinical trials registered in public databases. Based on current clinical experience and data, several scenarios of bacteriophage application for human therapy are examined. Finally, we discuss legislative hurdles in the regulatory approval process and present future perspectives for bacteriophage therapy. IMPLICATIONS: Antimicrobial resistance is one of the most important global public health challenges. Several different alternatives to conventional antibiotics are under development; bacteriophage therapy is one of them. Currently, therapeutic use of phages is restrained by regulatory hurdles and largely limited to sporadic authorization in compassionate use or under temporary approval as new drugs in Europe and the US. Although bacteriophage therapy seems to be safe and clinical results of phage treatment are promising, future data from high-quality (randomized controlled) trials could provide a better understanding of the reasonable minimal criteria required for expansion of bacteriophage therapy.

Use of negative pressure wound therapy in patients with fracture-related infection more than doubles the risk of recurrence.

PURPOSE: Fracture-related infection (FRI) is one of the most serious complications in orthopedic trauma surgery. Despite its widespread use, the role of Negative Pressure Wound Therapy (NPWT) remains controversial in the management pathway of FRI. The aim of this study was to assess the relationship between the application of NPWT and its duration and recurrence of infection in operatively treated FRI patients. PATIENTS AND METHODS: This is a retrospective cohort study based on the FRI database of three level 1 Trauma Centres. Included patients had to be at least 16 years of age and surgically treated for FRI between January 1st 2015 and September 1st 2020. Patients were subdivided in either the NPWT group, when NPWT was applied as part of the FRI treatment, or in the control group, when no NPWT had been applied. To limit confounding, patients were excluded if they (also) underwent NPWT prior to the diagnosis of FRI. The relation between the duration of NPWT during FRI treatment and the recurrence rate of infection was analyzed using a multivariable logistic regression model. RESULTS: A total of 263 patients were included, 99 in the NPWT group and 164 in the control group. The median duration of NPWT was 18.0 (IQR 15.8) days. In the NPWT group, 28 patients (28.3%) developed a recurrent FRI. In the control group, 19 patients (11.6%) had a recurrent FRI (p = 0.001, 95% CI [0.174 - 0.635]). In the NPWT group there were no significant differences in baseline characteristics between the recurrence and non-recurrence group. The duration of NPWT was associated with a higher risk of recurrence of infection (p = 0.013, OR 1.036, 95% CI [1.008 - 1.066]). CONCLUSION: Delayed wound closure with the application of NPWT increased the risk of recurrence of infection in patients with soft tissue defects after FRI treatment. Therefore, it is advised to consider NPWT only as a short-term (e.g. few days) necessity to bridge the period until definitive wound closure can be established.

Fracture-related infection.

Musculoskeletal trauma leading to broken and damaged bones and soft tissues can be a life-threating event. Modern orthopaedic trauma surgery, combined with innovation in medical devices, allows many severe injuries to be rapidly repaired and to eventually heal. Unfortunately, one of the persisting complications is fracture-related infection (FRI). In these cases, pathogenic bacteria enter the wound and divert the host responses from a bone-healing course to an inflammatory and antibacterial course that can prevent the bone from healing. FRI can lead to permanent disability, or long courses of therapy lasting from months to years. In the past 5 years, international consensus on a definition of these infections has focused greater attention on FRI, and new guidelines are available for prevention, diagnosis and treatment. Further improvements in understanding the role of perioperative antibiotic prophylaxis and the optimal treatment approach would be transformative for the field. Basic science and engineering innovations will be required to reduce infection rates, with interventions such as more efficient delivery of antibiotics, new antimicrobials, and optimizing host defences among the most likely to improve the care of patients with FRI.

The Microbiological Etiology of Fracture-Related Infection.

Purpose: Fracture-related infection (FRI) is an important complication related to orthopaedic trauma. Although the scientific interest with respect to the diagnosis and treatment of FRI is increasing, data on the microbiological epidemiology remains limited. Therefore, the primary aim of this study was to evaluate the microbiological epidemiology related to FRI, including the association with clinical symptoms and antimicrobial susceptibility data. The secondary aim was to analyze whether there was a relationship between the time to onset of infection and the microbiological etiology of FRI. Methods: FRI patients treated at the University Hospitals of Leuven, Belgium, between January 1st 2015 and November 24th 2019 were evaluated retrospectively. The microbiological etiology and antimicrobial susceptibility data were analyzed. Patients were classified as having an early (<2 weeks after implantation), delayed (2-10 weeks) or late-onset (> 10 weeks) FRI. Results: One hundred ninety-one patients with 194 FRIs, most frequently involving the tibia (23.7%) and femur (18.6%), were included. Staphylococcus aureus was the most frequently isolated pathogen, regardless of time to onset (n=61; 31.4%), followed by S. epidermidis (n=50; 25.8%) and non-epidermidis coagulase-negative staphylococci (n=35; 18.0%). Polymicrobial infections (n=49; 25.3%), mainly involving Gram negative bacilli (GNB) (n=32; 65.3%), were less common than monomicrobial infections (n=138; 71.1%). Virulent pathogens in monomicrobial FRIs were more likely to cause pus or purulent discharge (n=45;54.9%; p=0.002) and fistulas (n=21;25.6%; p=0.030). Susceptibility to piperacillin/tazobactam for GNB was 75.9%. Vancomycin covered 100% of Gram positive cocci. Conclusion: This study revealed that in early FRIs, polymicrobial infections and infections including Enterobacterales and enterococcal species were more frequent. A time-based FRI classification is not meaningful to estimate the microbiological epidemiology and cannot be used to guide empiric antibiotic therapy. Large multicenter prospective studies are necessary to gain more insight into the added value of (broad) empirical antibiotic therapy.

Ways to Improve Insights into Clindamycin Pharmacology and Pharmacokinetics Tailored to Practice.

Given the increase in bacterial resistance and the decrease in the development of new antibiotics, the appropriate use of old antimicrobials has become even more compulsory. Clindamycin is a lincosamide antibiotic approved for adults and children as a drug of choice for systemic treatment of staphylococcal, streptococcal, and gram-positive anaerobic bacterial infections. Because of its profile and high bioavailability, it is commonly used as part of an oral multimodal alternative for prolonged parenteral antibiotic regimens, e.g., to treat bone and joint or prosthesis-related infections. Clindamycin is also frequently used for (surgical) prophylaxis in the event of beta-lactam allergy. Special populations (pediatrics, pregnant women) have altered cytochrome P450 (CYP)3A4 activity. As clindamycin is metabolized by the CYP3A4/5 enzymes to bioactive N-demethyl and sulfoxide metabolites, knowledge of the potential relevance of the drug's metabolites and disposition in special populations is of interest. Furthermore, drug-drug interactions derived from CYP3A4 inducers and inhibitors, and the data on the impact of the disease state on the CYP system, are still limited. This narrative review provides a detailed survey of the currently available literature on pharmacology and pharmacokinetics and identifies knowledge gaps (special patient population, drug-drug, and drug-disease interactions) to describe a research strategy for precision medicine.