Exploration of the role of the penicillin binding protein 2c (Pbp2c) in inducible ß-lactam resistance in Corynebacteriaceae.

Six genes encoding putative high molecular weight penicillin-binding proteins (Pbp) are present in the genome of the ß-lactam-resistant strain Corynebacterium jeikeium K411. In this study, we show that pbp2c, one of these six genes, is present in resistant strains of Corynebacteriaceae but absent from sensitive strains. The molecular study of the pbp2c locus from C. jeikeium and its heterologous expression in Corynebacterium glutamicum allowed us to show that Pbp2c confers high levels of ß-lactam resistance to the host and is under the control of a ß-lactam-induced regulatory system encoded by two adjacent genes, jk0410 and jk0411. The detection of this inducible resistance may require up to 48 h of incubation, particularly in Corynebacterium amycolatum. Finally, the Pbp2c-expressing strains studied were resistant to all the ß-lactam antibiotics tested, including carbapenems, ceftaroline, and ceftobiprole.

Appropriateness of empirical antibiotic prescription for bloodstream infections in an emergency department from 2006 to 2018: impact of the spread of ESBL-producing Enterobacterales.

The spread of ESBL producers in the community may impact the management of patients with bloodstream infections (BSI) involving Enterobacterales in emergency departments. Thus, from 2006 to 2018, data for all BSI episodes involving Enterobacterales from the emergency department of a French teaching hospital were retrospectively included. Antimicrobial susceptibility test results and empirical antibiotic regimens were recorded. Treatment was considered as appropriate if all isolates were susceptible in vitro to at least one prescribed antibiotic. A total of 1369 BSI episodes in 1321 patients was included. Urinary tract infection was the main source of BSI (61%). The prevalence of ESBL producers increased from zero to 9.2/100 Enterobacterales BSI cases (p < 0.001), mainly Escherichia coli (6.9 cases/100 BSI in 2018); and no Klebsiella. Third-generation cephalosporins (3GC) were used most frequently (71.8%) and their use as monotherapy increased during the study period (p < 0.001). The rate of appropriate treatment decreased from 95.8 to 89.2% (p = 0.023). Appropriateness of treatment was greater using two drugs vs one (97.3% vs 89.3%, p < 0.001). Treatments with 3GC were appropriate in 92% and 98.3%, when used alone or with another antibiotic, respectively (p < 0.001). Among inappropriate treatments, 45% concerned 3GC, with 74.6% of them attributable to ESBL production. The spread of ESBL producers in the community had a direct impact on the rate of inappropriate empirical treatment. Local antimicrobial resistance monitoring is required to optimize the management of BSI in emergency departments.

A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

Renal abscess caused by Panton-Valentine leukocidin-producing Staphylococcus aureus: report of an unusual case and review of the literature.

BACKGROUND: Renal abscesses are rare and mainly caused by an ascending infection due to Gram-negative microorganisms. We report the first case of a renal abscess caused by Panton-Valentine leukocidin-producing Staphylococcus aureus in an immunocompetent patient, and we present a comprehensive review of the literature. CASE PRESENTATION: A 20-year-old immunocompetent woman had a 2-month history of left-sided back pain, fever and urinary symptoms. Urinalysis showed leukocyturia (19,000/mm3) without bacteriuria. Intravenous cefotaxime treatment was initiated. A computed tomographic scan showed a large abscess in the left kidney. Computed tomographic percutaneous drainage was done and cultures of abscess and blood grew methicillin-susceptible Panton-Valentine leukocidin-producing Staphylococcus aureus. Treatment was switched to cefazoline and then to clindamycin for 21 days. The patient quickly improved and the abscess was completely resolved 6 months after end of antibiotic treatment. CONCLUSION: To our knowledge, this is the first report of a renal abscess caused by Panton-Valentine leukocidin-producing Staphylococcus aureus. Treatment with percutaneous drainage and an antibiotic with toxin inhibiting effect was successful.

Ceftazidime-Avibactam Resistance Mediated by the N346Y Substitution in Various AmpC ß-Lactamases.

Chromosomal and plasmid-borne AmpC cephalosporinases are a major resistance mechanism to ß-lactams in Enterobacteriaceae and Pseudomonas aeruginosa The new ß-lactamase inhibitor avibactam effectively inhibits class C enzymes and can fully restore ceftazidime susceptibility. The conserved amino acid residue Asn346 of AmpC cephalosporinases directly interacts with the avibactam sulfonate. Disruption of this interaction caused by the N346Y amino acid substitution in Citrobacter freundii AmpC was previously shown to confer resistance to the ceftazidime-avibactam combination (CAZ-AVI). The aim of this study was to phenotypically and biochemically characterize the consequences of the N346Y substitution in various AmpC backgrounds. Introduction of N346Y into Enterobacter cloacae AmpC (AmpCcloacae), plasmid-mediated DHA-1, and P. aeruginosa PDC-5 led to 270-, 12,000-, and 79-fold decreases in the inhibitory efficacy (k2/Ki ) of avibactam, respectively. The kinetic parameters of AmpCcloacae and DHA-1 for ceftazidime hydrolysis were moderately affected by the substitution. Accordingly, AmpCcloacae and DHA-1 harboring N346Y conferred CAZ-AVI resistance (MIC of ceftazidime of 16 µg/ml in the presence of 4 µg/ml of avibactam). In contrast, production of PDC-5 N346Y was associated with a lower MIC (4 µg/ml) since this ß-lactamase retained a higher inactivation efficacy by avibactam in comparison to AmpCcloacae N346Y. For FOX-3, the I346Y substitution did not reduce the inactivation efficacy of avibactam and the substitution was highly deleterious for ß-lactam hydrolysis, including ceftazidime, preventing CAZ-AVI resistance. Since AmpCcloacae and DHA-1 display substantial sequence diversity, our results suggest that loss of hydrogen interaction between Asn346 and avibactam could be a common mechanism of acquisition of CAZ-AVI resistance.

Predictive factors of death associated with infective endocarditis in adult patients with congenital heart disease.

AIMS: Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease. METHODS AND RESULTS: Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, P<0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, P<0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, P<0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis. CONCLUSION: Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.

Predictive factors of death associated with infective endocarditis in adult patients with congenital heart disease.

AIMS: Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease. METHODS AND RESULTS: Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, P<0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, P<0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, P<0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis. CONCLUSION: Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.

Inhibition Activity of Avibactam against Nocardia farcinica ß-Lactamase FARIFM10152.

Nocardia farcinica, one of the most frequent pathogenic species responsible for nocardiosis, is characterized by frequent brain involvement and resistance to ß-lactams mediated by a class A ß-lactamase. Kinetic parameters for hydrolysis of various ß-lactams by FARIFM10152 from strain IFM 10152 were determined by spectrophotometry revealing a high catalytic activity (kcat/Km ) for amoxicillin, aztreonam, and nitrocefin. For cephems, kcat/Km was lower but remained greater than 104 M-1 s-1 A low catalytic activity was observed for meropenem, imipenem, and ceftazidime hydrolysis. FARIFM10152 inhibition by avibactam and clavulanate was compared using nitrocefin as a reporter substrate. FARIFM10152 was efficaciously inhibited by avibactam with a carbamoylation rate constant (k2/Ki ) of (1.7 ± 0.3) × 104 M-1 s-1 The 50% effective concentrations (EC50s) of avibactam and clavulanate were 0.060 ± 0.007 µM and 0.28 ± 0.06 µM, respectively. Amoxicillin, cefotaxime, imipenem, and meropenem MICs were measured for ten clinical strains in the presence of avibactam and clavulanate. At 4 µg/ml, avibactam and clavulanate restored amoxicillin susceptibility in all but one of the tested strains but had no effect on the MICs of cefotaxime, imipenem, and meropenem. At 0.4 µg/ml, amoxicillin susceptibility (MIC ≤ 8 µg/ml) was restored for 9 out of 10 strains by avibactam but only for 4 out of 10 strains by clavulanate. Together, these results indicate that avibactam was at least as potent as clavulanate, suggesting that the amoxicillin-avibactam combination could be considered as an option for the rescue treatment of N. farcinica infections if clavulanate cannot be used.

Accuracy of Curable Sexually Transmitted Infections and Genital Mycoplasmas Screening by Multiplex Real-Time PCR Using a Self-Collected Veil among Adult Women in Sub-Saharan Africa.

Background: Sexually transmitted infections (STIs) are highly prevalent in sub-Saharan Africa. Genital self-sampling may facilitate the screening of STIs in hard-to-reach remote populations far from large health care centers and may increase screening rates. The cross-sectional GYNAUTO-STI study was carried out to assess the performance of a novel genital veil (V-Veil-Up Gyn Collection Device, V-Veil-Up Pharma, Ltd., Nicosia, Cyprus) as a genital self-sampling device to collect genital secretions to diagnose STIs by molecular biology as compared to reference clinician-collected genital specimens, in adult African women. Methods: Adult women living in N'Djamena, the capital city of Chad, were recruited from the community and referred to the clinic for women's sexual health "La Renaissance Plus". A clinician obtained an endocervical specimen using flocked swab. Genital secretions were also obtained by self-collection using veil. Both clinician- and self-collected specimens were tested for common curable STIs (including Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium, and Trichomonas vaginalis) and genital Mycoplasma spp. by multiplex real-time PCR (Allplex™ STI Essential Assay, Seegene, Seoul, South Korea). Test positivities for both collection methods were compared by assessing methods agreement, sensitivity, and specificity. Results: A total of 251 women (mean age, 35.1 years) were prospectively enrolled. Only seven (2.8%) women were found to be infected with at least one common STIs [C. trachomatis: 3 (1.2%), N. gonorrhoeae: 1 (0.4%), M. genitalium: 4 (1.6%) and T. vaginalis: 1 (0.4%)], while the prevalence of genital mycoplasmas was much higher (54.2%) with a predominance of Ureaplasma parvum (42.6%). Self-collection by veil was non-inferior to clinician-based collection for genital microorganisms DNA molecular testing, with "almost perfect" agreement between both methods, high sensitivity (97.0%; 95%CI: 92.5-99.2%), and specificity (88.0%; 95%CI: 80.7-93.3%). Remarkably, the mean total number of genital microorganisms detected per woman was 1.14-fold higher in self-collected specimens compared to that in clinician-collected specimens. Conclusions: Veil-based self-collection of female genital secretions constitutes a convenient tool to collect in gentle way cervicovaginal secretions for accurate molecular detection of genital bacteria. Such sampling procedure could be easily implemented in STIs clinics in sub-Saharan Africa.

Spread of NDM-5 and OXA-181 Carbapenemase-Producing Escherichia coli in Chad.

We detected for the first time blaNDM-5 and blaOXA-181 in Escherichia coli isolates from hospitalized patients and healthy volunteers in Chad. These resistance genes were located on IncX3 and IncF plasmids. Despite the large diversity of E. coli clones, the identified resistant intestinal isolates belonged mainly to the same sequence type.

Synergistic in vitro activity between aztreonam and amoxicillin-clavulanate against Enterobacteriaceae-producing class B and/or class D carbapenemases with or without extended-spectrum ß-lactamases.

Introduction. Carbapenemase-producing Enterobacteriaceae have become a major public health concern over the last decade and treatment options are limited.Aims. We evaluated the synergistic activity of the combination of aztreonam (ATM) and clavulanate for 41 ß-lactam-resistant clinical isolates harbouring class B or/and class D carbapenemases combined or not with extended-spectrum ß-lactamases (ESBLs).Methodology. The MICs of ATM, with and without amoxicillin-clavulanate (AMC), were determined. Time-kill assays were performed for three representative strains.Results. The ATM-AMC combination had a synergistic effect on 34/41 (83 %) isolates. The MIC of ATM, in the presence of clavulanate, was ≤1 mg l-1 for 15/41 (37 %) isolates and ≤4 mg l-1 for 29/41 (71 %) isolates. Synergistic activity was observed for 34/37 (92 %) isolates producing ESBLs and carbapenemases, compared to 0/4 (0 %) for ESBL-negative strains. Complete or partial bactericidal activity was obtained when the MIC of the combination was 0.5 mg l-1 and 1.5 mg l-1 or 8 mg l-1, respectively.Conclusion. The combination of ATM and AMC could be an attractive unconventional treatment for infections due to carbapenemase- and ESBL-producing Enterobacteriaceae.

Tryptophan Fluorescence Quenching in ß-Lactam-Interacting Proteins Is Modulated by the Structure of Intermediates and Final Products of the Acylation Reaction.

In most bacteria, ß-lactam antibiotics inhibit the last cross-linking step of peptidoglycan synthesis by acylation of the active-site Ser of d,d-transpeptidases belonging to the penicillin-binding protein (PBP) family. In mycobacteria, cross-linking is mainly ensured by l,d-transpeptidases (LDTs), which are promising targets for the development of ß-lactam-based therapies for multidrug-resistant tuberculosis. For this purpose, fluorescence spectroscopy is used to investigate the efficacy of LDT inactivation by ß-lactams but the basis for fluorescence quenching during enzyme acylation remains unknown. In contrast to what has been reported for PBPs, we show here using a model l,d-transpeptidase (Ldtfm) that fluorescence quenching of Trp residues does not depend upon direct hydrophobic interaction between Trp residues and ß-lactams. Rather, Trp fluorescence was quenched by the drug covalently bound to the active-site Cys residue of Ldtfm. Fluorescence quenching was not quantitatively determined by the size of the drug and was not specific of the thioester link connecting the ß-lactam carbonyl to the catalytic Cys as quenching was also observed for acylation of the active-site Ser of ß-lactamase BlaC from M. tuberculosis. Fluorescence quenching was extensive for reaction intermediates containing an amine anion and for acylenzymes containing an imine stabilized by mesomeric effect, but not for acylenzymes containing a protonated ß-lactam nitrogen. Together, these results indicate that the extent of fluorescence quenching is determined by the status of the ß-lactam nitrogen. Thus, fluorescence kinetics can provide information not only on the efficacy of enzyme inactivation but also on the structure of the covalent adducts responsible for enzyme inactivation.

Performance evaluation of the ßLACTA™ Test for rapid detection of ceftazidime resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The chromogenic ßLACTA™ test was evaluated to detect ceftazidime resistance in P. aeruginosa isolates from patients with cystic fibrosis. Best results were obtained after one hour of incubation with low sensitivity (64.1%), high specificity (98.3%), and negative and positive predictive values of 80.3% and 96.2%, respectively.

Multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic ßLACTA test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the BLUE-CarbA protocol.

INTRODUCTION: The dramatic increase of the incidence of infections caused by extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) has led to an increase of 50% of carbapenem consumption all around Europe in only 5 years. This favours the spread of carbapenem-resistant Gram-negative bacilli (GNB), causing life-threatening infections. In order to limit use of carbapenems for infections actually due to ESBL-PE, health authorities promote the use of rapid diagnostic tests of bacterial resistance. The objective of this work conducted in the intensive care unit (ICU) is to determine whether an early de-escalation of empirical carbapenems guided by the result of the ßLACTA test is not inferior to the reference strategy of de-escalating carbapenems after the antibiogram result has been rendered. METHODS AND ANALYSIS: This multicentre randomised controlled open-label non-inferiority clinical trial will include patients suffering from respiratory and/or urinary and/or bloodstream infections documented with GNB on direct examination and empirically treated with carbapenems. Empirical carbapenems will be adapted before the second dose depending on the results of the ßLACTA test performed directly on the microbiological sample (intervention group) or after 48-72 hours depending on the definite antibiogram (control group). The primary outcome will combine 90-day mortality and percentage of infection recurrence during the ICU stay. The secondary outcomes will include the number of carbapenems defined daily doses and carbapenem-free days after inclusion, the proportion of new infections during ICU stay, new colonisation of patients' digestive tractus with multidrug-resistant GNB, ICU and hospital length of stay and cost-effectiveness ratio. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committee of Paris-Ile-de-France IV, and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03147807.

In vitro activity of ß-lactams in combination with avibactam against multidrug-resistant Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Achromobacter xylosoxidans isolates from patients with cystic fibrosis.

The in vitro activity of anti-pseudomonal ß-lactams in combination with avibactam was evaluated against 54 multidrug-resistant non-fermenting Gram-negative bacilli isolated from cystic fibrosis patients. Avibactam increased and/or restored the antibacterial activities of ceftazidime and aztreonam against Pseudomonas aeruginosa and Stenotrophomonas maltophilia, respectively. No ß-lactam-avibactam combination was active against Achromobacter xylosoxidans.

Combination of Amino Acid Substitutions Leading to CTX-M-15-Mediated Resistance to the Ceftazidime-Avibactam Combination.

Single amino acid substitutions in the Ω loop of KPC ß-lactamases are known to lead to resistance to the ceftazidime-avibactam combination. Here, we investigate this mechanism of resistance in CTX-M enzymes, which are the most widely spread extended-spectrum ß-lactamases worldwide. Nine single amino acid polymorphisms were identified in the Ω loop of the 172 CTX-M sequences present in the Lahey database of ß-lactamases. The corresponding modifications were introduced in CTX-M-15 by site-directed mutagenesis. None of the nine substitutions was associated with ceftazidime-avibactam resistance in Escherichia coli TOP10. However, two substitutions led to 4-fold (P167S) and 16-fold (L169Q) increases in the MIC of ceftazidime. We determined whether these substitutions favor the in vitro selection of mutants resistant to ceftazidime-avibactam. The selection provided mutants for the L169Q substitution but not for the P167S substitution or for the parental enzyme CTX-M-15. Resistance to the drug combination (MIC of ceftazidime, 16 µg/ml in the presence of 4 µg/ml of avibactam) resulted from the acquisition of the S130G substitution by CTX-M-15 L169Q. Purified CTX-M-15 with the two substitutions, L169Q and S130G, was only partially inhibited by avibactam at concentrations as high as 50,000 µM but retained ceftazidime hydrolysis activity with partially compensatory decreases in kcat and Km These results indicate that emergence of resistance to the ceftazidime-avibactam combination requires more than one mutation in most CTX-M-encoding genes. Acquisition of resistance could be restricted to rare variants harboring predisposing polymorphisms such as Q at position 169 detected in a single naturally occurring CTX-M enzyme (CTX-M-93).

Synthesis of Avibactam Derivatives and Activity on ß-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria.

There is a renewed interest for ß-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their ß-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 µg mL-1 for both species). Mechanistically, ß-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.

In vitro activity of tedizolid against the Mycobacterium abscessus complex.

Infections due to Mycobacterium abscessus carry a poor prognosis since this rapidly growing mycobacterium is intrinsically resistant to most antibiotics. Here, we evaluate the in vitro activity of the new oxazolidinone tedizolid against a collection of 44M. abscessus clinical isolates. The MIC50s and MIC90s of tedizolid (2 and 8µg/mL, respectively) were 2- to 16-fold lower than those of linezolid. There was no difference between the 3M. abscessus subspecies. Time-kill assays did not show any bactericidal activity at 4- and 8-fold the MIC. Combination of tedizolid with clarithromycin was synergistic against 1 out of 6 isolates, while indifferent interactions were observed for tedizolid combined with tigecycline, ciprofloxacin, and amikacin.

In vitro activity of tedizolid and comparator agents against Gram-positive pathogens responsible for bone and joint infections.

Tedizolid, a second-generation oxazolidinone that displays a potent activity against Gram-positive pathogens, could be an interesting option for the treatment of bone and joint infections (BJIs). The aim of the study was to determine minimal inhibitory concentration (MIC) of tedizolid against a collection of 359 clinical isolates involved in clinically-documented BJIs and to compare them to those of comparator agents used in Gram-positive infections. Of the 104 Staphylococcusaureus and 102 coagulase-negative staphylococci (CoNS) isolates, 99 and 92 % were categorized as susceptible to tedizolid, respectively (MIC25=0.12/0.25 µg ml-1 and MIC90=0.25/0.5 µg ml-1), regardless of their methicillin resistance. MIC50 and MIC90 for the 51 enterococci, the 50 Corynebacterium spp. and the 52 Propionibacterium spp. were either equal or inferior to 0.5 µg ml-1. Altogether, tedizolid possessed a potent in vitro activity against most of the BJI Gram-positive pathogens with 95 % of them exhibiting a MIC ≤0.5 µg ml-1.

Successful treatment of Pseudomonas aeruginosa osteomyelitis with antibiotic monotherapy of limited duration.

OBJECTIVES: The aim of this study was to present a 15-year experience and provide a comprehensive analysis of a large cohort of patients with Pseudomonas aeruginosa osteomyelitis. METHODS: We reviewed the medical records of patients admitted to a large French university hospital for P. aeruginosa osteomyelitis over a 15-year period. Patient outcome was assessed at follow-up after at least six months. RESULTS: Sixty-seven patients were included, comprising 57% with chronic osteomyelitis. Polymicrobial infection was predominant (63%), and an infected device was involved in 39% patients. The overall treatment success rate was 79.1%. All but one patient were treated with a combination of surgery and antibiotic therapy. The antibiotic treatment had a mean duration of 45 days (range, 21-90 days). Single-antibiotic therapy was preferred in nearly all cases. Treatment failure was reported for 14 (21%) patients and was due to the persistence of P. aeruginosa in four cases. No significant risk factor for treatment failure was identified, especially when treatment strategies were compared. CONCLUSIONS: We advocate optimal surgical debridement combined with initial parenteral antibiotics for a maximum of 15 days, followed by an oral fluoroquinolone. Total treatment duration should not exceed six weeks, and antibiotic treatment with two-drug combinations does not seem necessary.