Pharmacokinetic/Pharmacodynamic Dosage Individualization of Suppressive Beta-Lactam Therapy Administered by Subcutaneous Route in Patients With Prosthetic Joint Infection.

Suppressive parenteral antibiotic therapy with beta-lactams may be necessary in patients with Gram-negative bone and joint infection (BJI). Subcutaneous drug administration can facilitate this therapy in outpatient setting, but there is limited information about this practice. We have developed an original approach for drug dosing in this context, based on therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) principles. The objective of this study was to describe our approach and its first results in a case series. We analyzed data from patients who received suppressive antibiotic therapy by subcutaneous (SC) route with beta-lactams as salvage therapy for prosthetic joint infection (PJI) and had TDM with PK/PD-based dose adjustment. Ten patients (six women and four men with a mean age of 77 years) were included from January 2017 to May 2020. The drugs administered by SC route were ceftazidime (n = 4), ertapenem (n = 4), and ceftriaxone (n = 2). In each patient, PK/PD-guided dosage individualization was performed based on TDM and minimum inhibitory concentration (MIC) measurements. The dose interval could be prolonged from twice daily to thrice weekly in some patients, while preserving the achievement of PK/PD targets. The infection was totally controlled by the strategy in nine out the 10 patients during a median follow-up of 1,035 days (~3 years). No patient acquired carbapenem-resistant Gram-negative bacteria during the follow-up. One patient presented treatment failure with acquired drug resistance under therapy, which could be explained by late MIC determination and insufficient exposure, retrospectively. To conclude, our innovative approach, based on model-based TDM, MIC determination, and individualized PK/PD goals, facilitates, and optimizes suppressive outpatient beta-lactam therapy administered by SC route for PJI. These encouraging results advocate for larger clinical evaluation.

Impact on the Gut Microbiota of Intensive and Prolonged Antimicrobial Therapy in Patients With Bone and Joint Infection.

There is a growing interest in the potentially deleterious impact of antibiotics on gut microbiota. Patients with bone and joint infection (BJI) require prolonged treatment that may impact significantly the gut microbiota. We collected samples from patients with BJI at baseline, end of antibiotics (EOT), and 2 weeks after antibiotic withdrawal (follow-up, FU) in a multicenter prospective cohort in France. Microbiota composition was determined by shotgun metagenomic sequencing. Fecal markers of gut permeability and inflammation as well as multi-drug-resistant bacteria (MDRB) and Clostridioides difficile carriage were assessed at each time point. Sixty-two patients were enrolled: 27 native BJI, 14 osteosynthesis-related BJI, and 21 prosthetic joint infections (PJI). At EOT, there was a significant loss of alpha-diversity that recovered at FU in patients with native BJI and PJI, but not in patients with osteosynthesis-related BJI. At EOT, we observed an increase of Proteobacteria and Bacteroidetes that partially recovered at FU. The principal component analysis (PCoA) of the Bray-Curtis distance showed a significant change of the gut microbiota at the end of treatment compared to baseline that only partially recover at FU. Microbiota composition at FU does not differ significantly at the genus level when comparing patients treated for 6 weeks vs. those treated for 12 weeks. The use of fluoroquinolones was not associated with a lower Shannon index at the end of treatment; however, the PCoA of the Bray-Curtis distance showed a significant change at EOT, compared to baseline, that fully recovered at FU. Levels of fecal neopterin were negatively correlated with the Shannon index along with the follow-up (r 2 = 0.17; p < 0.0001). The PCoA analysis of the Bray-Curtis distance shows that patients with an elevated plasma level of C-reactive protein (≥5 mg/L) at EOT had a distinct gut microbial composition compared to others. MDRB and C. difficile acquisition at EOT and FU represented 20% (7/35) and 37.1% (13/35) of all MDRB/C. difficile-free patients at the beginning of the study, respectively. In patients with BJI, antibiotics altered the gut microbiota diversity and composition with only partial recovery, mucosal inflammation, and permeability and acquisition of MDRB carriage. Microbiome interventions should be explored in patients with BJI to address these issues.

Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.

Slowly or Nonresolving Legionnaires' Disease: Case Series and Literature Review.

BACKGROUND: Rarely, Legionnaires' disease (LD) can progress into a slowly or nonresolving form. METHODS: A nationwide retrospective study was conducted by the French National Reference Center for Legionella (2013-2017) including cases of slowly or nonresolving LD defined as persistent clinical symptoms, computed tomography (CT) scan abnormalities, and Legionella detection in lower respiratory tract specimens by culture and/or real-time (RT) polymerase chain reaction (PCR) >30 days after symptom onset. RESULTS: Twelve cases of community-acquired slowly or nonresolving LD were identified among 1686 cases of culture-positive LD. Median (interquartile range [IQR]) age was 63 (29-82) years. Ten (83.3%) patients had ≥1 immunosuppressive factor. Clinically, 9 patients transiently recovered before further deterioration (median [IQR] symptom-free interval, 30 [18-55] days), 3 patients had uniformly persistent symptoms (median [IQR] time, 48 [41.5-54] days). Two patients had >2 recurrences. CT scan imagery found lung abscess in 5 (41.6%) cases. Slowly or nonresolving LD was diagnosed on positive Legionella cultures (n = 10, 83.3%) at 49.5 (IQR, 33.7-79) days. Two cases were documented through positive Legionella RT PCR at 52 and 53 days (cycle threshold detection of 21.5 and 33.7, respectively). No genomic microevolution and no Legionella resistance to antibiotics were detected. The median (IQR) duration of treatment was 46.5 (21-92.5) days. Two empyema cases required thoracic surgery. At a median (IQR) follow-up of 26 (14-41.5) months, LD-attributable mortality was 16.6% (n = 2). CONCLUSIONS: Slowly or nonresolving LD may occur in immunocompromised patients, possibly leading to lung abscess and empyema.

Subcutaneous suppressive antibiotic therapy for bone and joint infections: safety and outcome in a cohort of 10 patients.

BACKGROUND: Optimal treatment of prosthetic joint infection and chronic osteomyelitis consists of surgical removal of biofilm-embedded bacteria, followed by a 6-12 week course of antimicrobial therapy. However, when optimal surgery is not feasible, oral prolonged suppressive antibiotic therapy (PSAT) is recommended to prevent prosthesis loosening and/or relapse of infection. Since 2010, we have used infection salvage therapy using off-label subcutaneous (sc) injection of a ß-lactam as PSAT for patients in whom oral PSAT is not possible. METHODS: A single-centre prospective cohort study (2010-18) reporting treatment modalities, efficacy and safety in all patients receiving sc PSAT. NCT03403608. RESULTS: The 10 included patients (median age 79 years) had polymicrobial (n = 5) or MDR bacterial (n = 4) prosthetic joint infection (knee, n = 4; hip, n = 3) or chronic osteomyelitis (n = 3). After initial intensive therapy, seven patients received ertapenem, three patients received ceftriaxone and one patient received ceftazidime by sc injection (one patient received 8 days of ceftriaxone before receiving ertapenem). In one patient, sc PSAT failed with recurrent signs of infection under treatment. In three patients, sc PSAT had to be discontinued due to side effects; in only one of these was the sc route implicated (skin necrosis following direct sc injection and not gravity infusion). Median treatment duration was 433 days. In six patients, sc PSAT was successful with favourable outcome at the time of writing. Interestingly, three patients with MDR bacterial carriage at baseline lost this under PSAT during follow-up. CONCLUSIONS: As salvage therapy, sc PSAT delivered by gravity infusion is a safe and interesting alternative when an optimal surgical strategy is not feasible and no oral treatment is available.