Necrotizing external otitis: analysis of relapse risk factors in 66 patients managed during a 12 year period.

BACKGROUND: Necrotizing external otitis (NEO) is a severe infection of the skull base that occurs generally in the elderly and/or in diabetic recipients. There are few data in the literature about the therapeutic management of this complex bone infection. OBJECTIVES: To analyse relapses after NEO treatment completion, and to describe the clinical features of NEO. METHODS: We performed a retrospective cohort study in the Lyon regional reference centre for the management of complex bone and joint infections. Consecutive cases of NEO from 1 January 2006 to 31 December 2018 were included. The primary outcome was the relapse of NEO. Variables were analysed using Cox regression survival analysis with adjusted hazard ratio (aHR) and Kaplan-Meier curve. RESULTS: Sixty-six patients were included. Median age was 75 (IQR 69-81) years and 46 (70%) patients were diabetic. Eleven patients (17%) had temporomandibular arthritis, 10 (15%) cranial nerve paralysis, 2 (3%) cerebral thrombophlebitis, and 2 (3%) contiguous abscess. Microbiological documentation was obtained in 56 patients and revealed Pseudomonas aeruginosa in 44/56 patients (79%). Nine (14%) cases had no microbiological documentation. Antibiotic therapy was dual for 63 (95%) patients. During a median follow-up of 27 (IQR 12-40) months, 16 out of 63 (25%) patients experienced a relapse. Fungal infection was significantly associated with relapse [aHR 4.1 (95% CI 1.1-15); P = 0.03]. CONCLUSIONS: NEO is a severe bone infection, mainly (but not exclusively) caused by P. aeruginosa, which occurs in elderly and diabetic recipients. Fungal infections at baseline significantly impact the outcome.

Long-term use of liposomal nebulized amikacin and tedizolid for the treatment of disseminated nocardiosis after allogeneic hematopoietic stem cell transplantation.

Nocardiosis is a life-threatening opportunistic infection in immunocompromised patients. Herein, we present successful adjunctive use of liposomal nebulized amikacin and tedizolid in a recipient of allogeneic hematopoietic stem cell transplantation infected with Nocardia nova complex who presented multiple complications to conventional therapeutic options.

Genetic polymorphisms of ABCB1 (P-glycoprotein) as a covariate influencing daptomycin pharmacokinetics: a population analysis in patients with bone and joint infection.

BACKGROUND: Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK). OBJECTIVES: We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI. PATIENTS AND METHODS: We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets. RESULTS: Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy. CONCLUSIONS: Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements.

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.

Prospective Cohort Study of the Tolerability of Prosthetic Joint Infection Empirical Antimicrobial Therapy.

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin (n = 229, 68.8%), piperacillin-tazobactam (n = 131, 39.3%), and/or third-generation cephalosporins (n = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE (n = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.).

Pressure ulcer-related pelvic osteomyelitis: evaluation of a two-stage surgical strategy (debridement, negative pressure therapy and flap coverage) with prolonged antimicrobial therapy.

BACKGROUND: A two-stage surgical strategy (debridement-negative pressure therapy (NPT) and flap coverage) with prolonged antimicrobial therapy is usually proposed in pressure ulcer-related pelvic osteomyelitis but has not been widely evaluated. METHODS: Adult patients with pressure ulcer-related pelvic osteomyelitis treated by a two-stage surgical strategy were included in a retrospective cohort study. Determinants of superinfection (i.e., additional microbiological findings at reconstruction) and treatment failure were assessed using binary logistic regression and Kaplan-Meier curve analysis. RESULTS: Sixty-four pressure ulcer-related pelvic osteomyelitis in 61 patients (age, 47 (IQR, 36-63)) were included. Osteomyelitis was mostly polymicrobial (73%), with a predominance of S. aureus (47%), Enterobacteriaceae spp. (44%) and anaerobes (44%). Flap coverage was performed after 7 (IQR, 5-10) weeks of NPT, with 43 (68%) positive bone samples among which 39 (91%) were superinfections, associated with a high ASA score (OR, 5.8; p = 0.022). An increased prevalence of coagulase negative staphylococci (p = 0.017) and Candida spp. (p = 0.003) was observed at time of flap coverage. An ESBL Enterobacteriaceae spp. was found in 5 (12%) patients, associated with fluoroquinolone consumption (OR, 32.4; p = 0.005). Treatment duration was as 20 (IQR, 14-27) weeks, including 11 (IQR, 8-15) after reconstruction. After a follow-up of 54 (IQR, 27-102) weeks, 15 (23%) failures were observed, associated with previous pressure ulcer (OR, 5.7; p = 0.025) and Actinomyces spp. infection (OR, 9.5; p = 0.027). CONCLUSIONS: Pressure ulcer-related pelvic osteomyelitis is a difficult-to-treat clinical condition, generating an important consumption of broad-spectrum antibiotics. The lack of correlation between outcome and the debridement-to-reconstruction interval argue for a short sequence to limit the total duration of treatment.

Diagnostic, clinical management, and outcome of bone flap-related osteomyelitis after cranioplasty.

OBJECTIVES: We aimed to describe diagnostic, management, and outcome of bone flap-related osteomyelitis after cranioplasty. METHODS: Patients followed up in our tertiary care hospital for bone flap-related osteomyelitis after cranioplasty were included in a retrospective cohort (2008-2021). Determinants of treatment failure were assessed using logistic regression and Kaplan-Meier curves analysis. RESULTS: The 144 included patients (81 [56.3%] males; median age 53.4 [interquartile range [IQR], 42.6-62.5] years) mostly presented wound abnormalities (n = 115, 79.9%). All infections were documented, the main pathogens being Staphylococcus aureus (n = 64, 44.4%), Cutibacterium acnes (n = 57, 39.6%), gram-negative bacilli (n = 40, 27.8%) and/or non-aureus staphylococci (n = 34, 23.6%). Surgery was performed in 140 (97.2%) cases, for bone flap removal (n = 102, 72.9%) or debridement with flap retention (n = 31, 22.1%), along with 12.7 (IQR, 8.0-14.0) weeks of antimicrobial therapy. After a follow-up of 117.1 (IQR, 62.5-235.5) weeks, 37 (26.1%) failures were observed: 16 (43.2%) infection persistence, three (8.1%) relapses, 22 (59.5%) superinfections and/or two (1.7%) infection-related deaths. Excluding superinfections, determinants of the 19 (13.4%) specific failures were an index craniectomy for brain tumor (odds ratio = 4.038, P = 0.033) and curettage of bone edges (odds ratio = 0.342, P = 0.048). CONCLUSION: Post-craniectomy bone flap osteomyelitis are difficult-to-treat infection, necessitating prolonged antimicrobial therapy with appropriate surgical debridement, and advocating for multidisciplinary management in dedicated reference centers.

Prognosis and factors associated with disseminated nocardiosis: a ten-year multicenter study.

OBJECTIVES: Nocardiosis is a rare opportunistic infection that is frequently associated with dissemination (i.e. involvement of several body sites). Identifying the factors associated with Nocardia spp. dissemination may help improving the management of patients with nocardiosis. METHODS: This 10-year (2010-2020) retrospective multicenter cohort study included adult patients with Nocardia-confirmed infections. The first objective was to determine the factors associated with disseminated nocardiosis. The secondary endpoints were to determine and compare the management and the 12-month overall mortality in patients with localized and disseminated nocardiosis. Univariate and multivariate logistic regression analyses were used. RESULTS: Nocardia spp. infection was confirmed in 110 patients, of whom 38 (34.5%) had disseminated nocardiosis. In univariate analysis, the factors associated with dissemination were immunosuppressive conditions: having an auto-immune disease and receiving high-dose corticosteroid (31.5% vs 8.3%, P = 0.003 and 52.6% vs 26.3%, P = 0.007, respectively). Absolute lymphocyte count <1 G/L at diagnosis was the only biomarker associated with dissemination (57.2% vs 26.3%, P = 0.007). Nocardia farcinica was not only the most frequent species identified in patient specimens (n = 22, 20%) but was also associated with a higher rate of dissemination (36.8% vs 11.1%, P = 0.002). Multivariate analysis confirmed the association between auto-immune diseases, lymphopenia, N. farcinica species and the higher rate of dissemination. Even though patients with disseminated nocardiosis were treated longer and more often with an antibiotic combination therapy, their 12-month overall mortality was significantly higher than that of patients with localized nocardiosis (36.8% vs 18%). CONCLUSIONS: Dissemination of Nocardia spp. is favoured by auto-immune diseases, lymphopenia, and infection with N. farcinica.

Pseudomonas aeruginosa Implant-Associated Bone and Joint Infections: Experience in a Regional Reference Center in France.

Background: P. aeruginosa implant-associated bone and joint infections (BJI) is considered to be one of the most difficult to treat BJI. The data focusing specifically on this pathogen are sparse, and it seems difficult to extrapolate the results obtained with Enterobacteriaceae. Methods: We performed a retrospective observation study of all P. aeruginosa implant-associated BJI diagnosed at our institution from 2011 to 2018. We defined failure as any type of relapse, including persistence of the same P. aeruginosa, superinfection by another organism(s) or any other cause of relapse such as the need for a subsequent surgery. Nonparametric statistical methods were used to compare the study groups and Kaplan-Meier curves and multivariate Cox analysis and were used to detect determinants associated with treatment failure. Results: A total of 90 patients (62% men, median age 60 years IQR 47-72) including 30 (33%) prosthetic-joint infections and 60 (66%) other implant-associated BJIs were studied. Most of them were acute (62%). During the prolonged follow-up, (median 20 months; IQR 9-37), 23 patients (26%) experienced treatment failure. Optimal surgical treatment (DAIR for acute forms, explantation, 1-stage or 2-stage exchange for others) was significantly associated with a higher success rate in the univariate analysis (p = 0.003). Sixty-four (71%) patients received effective initial treatment against P. aeruginosa administered and 81 of them (90%) did for at least 3 weeks: both these parameters correlated with a higher success rate. In the multivariate Cox-analysis optimal surgical treatment, IV effective treatment of at least 3 weeks and treatment with ciprofloxacin for at least 3 months proved to be independently associated to a better outcome in patients with P. aeruginosa implant-associated BJI. Conclusion: P. aeruginosa implant-associated BJI is one of the most difficult-to-treat BJI, with a strong impact on the prognosis of the surgical strategy. An effective initial IV antibiotic treatment for at least 3 weeks seems to be required, followed by oral ciprofloxacin for a total duration of 3 months.