Pharmacokinetic interaction between rifampicin and clindamycin in staphylococcal osteoarticular infections.

OBJECTIVES: Oral combination of clindamycin and rifampicin is relevant for the treatment of staphylococcal osteoarticular infection (SOAIs). However, rifampicin induces CYP3A4, suggesting a pharmacokinetic interaction with clindamycin with unknown pharmacokinetic/pharmacodynamic (PK/PD) consequences. This study aimed to quantify clindamycin PK/PD markers before and during rifampicin co-administration in SOAI. METHODS: Patients with SOAI were included. After initial intravenous antistaphylococcal treatment, oral therapy was started with clindamycin (600 or 750 mg t.i.d.), followed by addition of rifampicin 36 h later. Population PK analysis was performed using the SAEM algorithm. PK/PD markers were compared with and without rifampicin co-administration, each patient being his own control. RESULTS: In 19 patients, clindamycin median (range) trough concentrations were 2.7 (0.3-8.9) mg/L and <0.05 (<0.05-0.3) mg/L before and during rifampicin administration, respectively. Rifampicin co-administration increased clindamycin clearance by a factor 16 and reduced the AUC0-8h/MIC by a factor 15 (P < 0.005). Clindamycin plasma concentrations were simulated for 1000 individuals, without and with rifampicin. Against a susceptible Staphylococcus aureus strain (clindamycin MIC 0.0625 mg/L), >80% of individuals would reach all proposed PK/PD targets without co-administration of rifampicin, even with low clindamycin dose. For the same strain, when rifampicin was co-administered, the probability to reach clindamycin PK/PD targets dropped to 1% for %fT>MIC = 100% and to 6% for AUC0-24h/MIC > 60, even with high clindamycin dose. CONCLUSION: Rifampicin co-administration with clindamycin has a high impact on clindamycin exposure and PK/PD targets in SOAI, which could result in clinical failure even for fully susceptible strains.

Treatment With a Three-Drug Regimen for Pulmonary Tuberculosis Based on Rapid Molecular Detection of Isoniazid Resistance: A Noninferiority Randomized Trial (FAST-TB).

Background: The rationale behind the use of ethambutol in the standard tuberculosis treatment is to prevent the emergence of resistance to rifampicin in case of primary resistance to isoniazid. We evaluated whether early detection of isoniazid resistance using molecular testing allows the use an ethambutol-free regimen. Methods: FAST-TB, a phase 4, French, multicenter, open-label, non-inferiority trial, compared 2 strategies: (1) polymerase chain reaction (PCR)-based detection of isoniazid and rifampicin resistance at baseline using Genotype MTBDRplus version 2.0 followed by ethambutol discontinuation if no resistance was detected (PCR arm) and (2) a standard 4-drug combination, pending phenotypic drug-susceptibility results (C arm). Adult patients with smear-positive pulmonary tuberculosis were enrolled. The primary endpoint was the proportion of patients with treatment success defined as bacteriological or clinical cure at the end of treatment. A non-inferiority margin of 10% was used. Results: Two hundred three patients were randomized, 104 in the PCR arm and 99 in the C arm: 26.6% were female, median age was 37 (interquartile range, 28-51) years, 72.4% were born in Africa, and 5.4% were infected with human immunodeficiency virus. Chest x-ray showed cavities in 64.5% of the cases. Overall, 169 patients met criteria of treatment success: 87 of 104 (83.7%) in the PCR arm and 82 of 99 (82.8%) in the C arm with a difference of +0.8% (90% confidence interval, -7.9 to 9.6), meeting the noninferiority criteria in the intention-to-treat population (P = .02). Conclusions: In a setting with low prevalence of primary isoniazid resistance, a 3-drug combination with isoniazid, rifampicin, and pyrazinamide, based on rapid detection of isoniazid resistance using molecular testing, was noninferior to starting the recommended 4-drug regimen.

Tuberculosis trends in a hot-spot region in Paris, France.

SETTING: Tuberculosis (TB) incidence is declining overall in France, but not in Paris where some areas remain relative hot spots for TB.OBJECTIVES: To obtain a better knowledge of local TB epidemiology in order to facilitate control measures.DESIGN: Analysis of demographic data of TB patients diagnosed at the Bichat-Claude Bernard Hospital from 2007 to 2016, with spoligotyping of Mycobacterium tuberculosis complex isolates.RESULTS: During the study period, 1096 TB patients were analysed. The incidence of TB diagnosis was stable, averaging 115 patients per year, predominantly males (71%), foreign-born (81%), with pulmonary TB (77%) and negative HIV serology (88%). The mean age of foreign-born TB patients decreased over the study period, most significantly in recent arrivals in France, whose average age decreased by two years (P = 0.001). The time period between arrival in France and being diagnosed with active TB decreased annually significantly by 0.75 years (P = 0.02). The proportion of L4.6.2/Cameroon and L2/Beijing sub-lineages increased annually by 0.7% (P < 0.05). Multi-drug resistant strains, representing 4% of all strains, increased annually by 0.75% (P = 0.03)CONCLUSION: The number of TB patients remained high in northern Paris and the surrounding suburbs, suggesting the need for increased control measures.

Long-term plasma pharmacokinetics of bedaquiline for multidrug- and extensively drug-resistant tuberculosis.

SETTING: Bedaquiline (BDQ) has been approved for the treatment of multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB). For many patients treatment is prolonged beyond the recommended 6 months. The long-term pharmacokinetics of BDQ have yet to be elucidated. OBJECTIVE: To evaluate plasma concentrations of BDQ during treatment and its elimination after treatment discontinuation. DESIGN: This was a retrospective study conducted in two units in France that provide treatment for MDR/XDR-TB. Sociodemographic, clinical, biological and therapeutic parameters were collected from patients currently or formerly treated with BDQ. Plasma concentrations of BDQ and its active M2 (N-desmethyl) metabolite were determined using ultra-performance liquid chromatography with tandem mass spectrometry. RESULTS: Thirteen patients were recruited (35 samples): 10 (31 samples) during BDQ treatment and 3 (4 samples) after BDQ discontinuation. The median duration of treatment with BDQ was 11 months (interquartile range [IQR] 8-14). During treatment, the median plasma BDQ concentrations and M2 were respectively 1264 ng/ml (IQR 910-2244) and 252 ng/ml (IQR 134-290). In one patient, BDQ was detected in the plasma 200 days after treatment discontinuation (528 ng/ml). CONCLUSION: BDQ and M2 plasma concentrations were consistent with good drug efficacy/safety profiles, suggesting good treatment adherence with no relevant drug interactions. The long-term plasma detectability of BDQ after treatment discontinuation may raise the spectre of the emergence of resistance.

Contribution of brain imaging to the diagnosis of intracranial tuberculoma and other brain lesions in patients presenting with miliary tuberculosis.

BACKGROUND: Miliary tuberculosis (miliary TB) is characterized by a hematogenous spread of Mycobacterium tuberculosis. Cerebral lesions associated with miliary TB have been reported with diverse frequencies. METHODS: We retrospectively analyzed brain imaging in 34 patients presenting with proven miliary TB hospitalized in our teaching hospital between 2008 and 2014. RESULTS: Neurological symptoms were present at admission in 15 patients, emerged during treatment in six, and were never reported in 13. Twenty-one of 34 patients had cerebral involvement, of which five patients did not present with any neurological symptoms. The most common brain lesions on MRI were tuberculomas. Cerebrospinal fluid (CSF) analysis showed elevated cell count in eight patients who all had abnormal MRI results. Nine patients with normal CSF had abnormal MRI results. CSF cultures were positive in only eight patients. Paradoxical clinical worsening during TB and corticosteroid treatment was observed in six patients. CONCLUSION: Among patients presenting with miliary TB who underwent brain imaging, more than 60% demonstrated cerebral involvement. Abnormal imaging could occur without any clinical nor CSF impairment. Systematically performing brain imaging in miliary TB patients could therefore be informative.

Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review.

BACKGROUND: Anti-staphylococcal penicillins (ASPs) are recommended as first-line agents in methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Concerns about their safety profile have contributed to the increased use of cefazolin. The comparative clinical effectiveness and safety profile of cefazolin versus ASPs for such infections remain unclear. Furthermore, uncertainty persists concerning the use of cefazolin due to controversies over its efficacy in deep MSSA infections and its possible negative ecological impact. AIMS: The aim of this narrative review was to gather and balance available data on the efficacy and safety of cefazolin versus ASPs in the treatment of MSSA bacteraemia and to discuss the potential negative ecological impact of cefazolin. SOURCES: PubMed and EMBASE electronic databases were searched up to May 2017 to retrieve available studies on the topic. CONTENTS: Although described in vitro and in experimental studies, the clinical relevance of the inoculum effect during cefazolin treatment of deep MSSA infections remains unclear. It appears that there is no significant difference in rate of relapse or mortality between ASPs and cefazolin for the treatment of MSSA bacteraemia but these results should be cautiously interpreted because of the several limitations of the available studies. Compared with cefazolin, there is more frequent discontinuation for adverse effects with ASP use, especially because of cutaneous and renal events. No study has evidenced any change in the gut microbiota after the use of cefazolin. IMPLICATIONS: Based on currently available studies, there are no data that enable a choice to be made of one antibiotic over the other except in patients with allergy or renal impairment. This review points out the need for future prospective studies and randomized controlled trials to better address these questions.

Unexpected persistence of extended-spectrum ß-lactamase-producing Enterobacteriaceae in the faecal microbiota of hospitalised patients treated with imipenem.

Imipenem is active against extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) but favours the intestinal emergence of resistance. The effects of imipenem on intestinal microbiota have been studied using culture-based techniques. In this study, the effects were investigated in patients using culture and metagenomic techniques. Seventeen hospitalised adults receiving imipenem were included in a multicentre study (NCT01703299, http://www.clinicaltrials.gov). Most patients had a history of antibiotic use and/or hospitalisation. Stools were collected before, during and after imipenem treatment. Bacterial and fungal colonisation was assessed by culture, and microbiota changes were assessed using metagenomics. Unexpectedly, high colonisation rates by imipenem-susceptible ESBL-E before treatment (70.6%) remained stable over time, suggesting that imipenem intestinal concentrations were very low. Carriage rates of carbapenem-resistant Gram-negative bacilli (0-25.0%) were also stable over time, whereas those of yeasts (64.7% before treatment) peaked at 76.5% during treatment and decreased thereafter. However, these trends were not statistically significant. Yeasts included highly diverse colonising Candida spp. Metagenomics showed no global effect of imipenem on the bacterial taxonomic profiles at the sequencing depth used but demonstrated specific changes in the microbiota not detected with culture, attributed to factors other than imipenem, including sampling site or treatment with other antibiotics. In conclusion, culture and metagenomics were highly complementary in characterising the faecal microbiota of patients. The changes observed during imipenem treatment were unexpectedly limited, possibly because the microbiota was already disturbed by previous antibiotic exposure or hospitalisation.

Score for pulmonary tuberculosis in patients with clinical presumption of tuberculosis in a low-prevalence area.

OBJECTIVES: To develop a diagnostic predictive model for the identification of patients with presumptive pulmonary tuberculosis (PTB) at high risk for active disease and those requiring nucleic acid amplification (NAAT) testing and/or preventive respiratory isolation in low-incidence, high-income countries. DESIGN: A 1:1 case-control study was conducted in consecutive immunocompetent patients with presumed PTB hospitalised between 2009 and 2012 in Paris, France. Cases were defined as individuals with culture-confirmed PTB, regardless of smear result. Those with presumed PTB and three smear- and culture-negative samples were selected as controls. A score was derived using conditional logistic regression. Internal validity of the score was assessed using the bootstrap method. RESULTS: A total of 354 patients were included in the analysis (177 cases, 177 controls). Among the 177 cases, 74 (42%) were smear-negative but culture-positive. Factors independently associated with PTB were age <50 years (adjusted OR [aOR] 4.7, 95%CI 1.8-12), diabetes (aOR 3.2, 95%CI 1.1-9.8), absence of cough with or without sputum (aOR 3.7, 95%CI 1.7-8.3), fever >15 days (aOR 3.5, 95%CI 1.3-9.5), apical infiltration without cavity (aOR 3.4, 95%CI 1.4-8.5) and cavitation or miliary pattern (aOR 19.7, 95%CI 7.6-51.1). Score C-index was 0.84 (95%CI 0.79-0.88). Calibration for the overall population (P = 0.770) and in smear-negative patients (P = 0.980) was appropriate. A score of 3.3 had 90% sensitivity, 50% specificity and 79% (IQR 28-95) median probability of PTB. CONCLUSIONS: This score could be used to build an algorithm to determine the need for respiratory isolation and/or NAAT use in PTB disease.

Mitral endocarditis due to Rothia aeria with cerebral haemorrhage and femoral mycotic aneurysms, first French description.

Rothia aeria is a Rothia species from the Micrococcaceae family. We report here the first French R. aeria endocarditis complicated by brain haemorrhage and femoral mycotic aneurysms. Altogether, severity and antimicrobial susceptibility should make us consider the management of R. aeria endocarditis as Staphylococcus aureus methicillin-susceptible endocarditis.

Prevention of urinary tract infections by antibiotic cycling in spinal cord injury patients and low emergence of multidrug resistant bacteria.

BACKGROUND: Urinary tract infections (UTIs) are a major recurrent problem for spinal cord injury (SCI) patients. Repeated antibiotic treatments contribute to the emergence of multidrug-resistant bacteria (MDRB). We evaluated the use of weekly oral cycling antibiotics (WOCA) in the prevention of UTIs over a mean follow-up period of 53 months (median follow-up period: 57 months) and analyzed the risk of MDRB emergence. METHODS: We conducted a cross-sectional study of adult SCI patients with neurogenic bladder who were receiving the WOCA regimen. RESULTS: We included 50 patients, mainly men (60%), with a mean age of 51±13.5 years. Overall, 66% of patients had been paraplegic or tetraplegic for 19.4±14.3 years; 92% underwent intermittent catheterization; and 36% had no postvoid residual. The number of febrile and non-febrile UTIs significantly reduced after WOCA initiation (9.45 non-febrile UTIs before WOCA initiation vs. 1.57 after; 2.25 febrile UTIs before WOCA initiation vs. 0.18 after; P=0.0001). Only one adverse event was reported during the follow-up period. The number of MDRB-colonized patients decreased from 9/50 to 4/50 during the follow-up period. CONCLUSION: WOCA is an effective and safe strategy to prevent UTIs in SCI patients with neurogenic bladder. WOCA does not lead to the emergence of MDRB resistance and even seems to reduce MDRB carriage.

Epidemiology and risk factors of multidrug-resistant bacteria in respiratory samples after lung transplantation.

BACKGROUND: Multidrug-resistant (MDR) bacteria are a growing concern worldwide. The aim of this study was to describe the epidemiology and risk factors of MDR bacteria detected in respiratory invasive samples during hospitalization in the intensive care unit (ICU) after lung transplantation (LT). METHODS: This study was based on a retrospective analysis of 176 patients hospitalized in the ICU after LT in 2006-2012. Respiratory invasive samples were performed according to a routine protocol. MDR pathogens were defined according to in vitro susceptibility tests. RESULTS: A total of 1176 bacteria were cultured. Susceptibility testing was performed on 1046 strains and 404 (39%) MDR were detected in 90 (51%) patients. Pseudomonas aeruginosa, coagulase-negative staphylococci, and Enterobacteriaceae (mainly Enterobacter species) were the most common MDR pathogens. On multivariate analysis, an ICU stay >14 days, presence of a tracheostomy, and previous exposure to broad-spectrum antibiotics were associated with MDR acquisition (odds ratio [OR] 3.7; 95% confidence interval [1.69-8.12]; OR 3.28 [1.05-10.28]; and OR 2.25 [1.17-4.34], respectively). We consistently observed an increasing emergence of resistance to several antibiotics, from week 1 to week 4 of ICU hospitalization: for ticarcillin, piperacillin-tazobactam, ceftazidime, imipenem/cilastatin, amikacin, and ciprofloxacin in P. aeruginosa; and for piperacillin-tazobactam, cefepime, and amikacin in Enterobacteriaceae. CONCLUSION: A large proportion of MDR bacteria are detected on respiratory invasive samples in LT patients, and the risk of their emergence is mainly determined by the previous exposure to broad-spectrum antibiotics and the length of ICU stay. Adequate treatment requires broad-spectrum empiric antibiotic therapy.

Evidence of a clonal expansion of Streptococcus pneumoniae serotype 19A in adults as in children assessed by the DiversiLab® system.

Streptococcus pneumoniae serotype 19A was the main serotype responsible for invasive pneumococcal disease (IPD) in the Paris area in 2007 and 2009 in both adults and children. To verify if a particular clone is emerging, we determined the populational structure of S. pneumoniae isolates. Eighty-four S. pneumoniae strains responsible for invasive infections isolated from 52 adults and 32 children hospitalized in Parisian hospitals were analyzed. Capsular typing was performed by polymerase chain reaction (PCR) using the semi-automated repetitive sequence-based (rep-PCR) DiversiLab® System. Multilocus sequence typing (MLST) was also performed on 26 strains (ten selected strains after cluster analysis and 16 control strains). In 2007 and 2009, S. pneumoniae serotype 19A represented, respectively, 28.6 % and 25 % of the serotypes involved in IPDs in children and 13 % and 13.7 % in adults. The rep-PCR DiversiLab® analysis showed that the 84 S. pneumoniae serotype 19A isolates were distributed in five clusters and four unique rep-PCR types. Overall, 77/84 (91.6 %) S. pneumoniae 19A serotypes grouped into three main genetically related clusters (71/77 belonged to the cluster I). The five other strains exhibited different profiles. Using MLST, we demonstrated that most strains of the main cluster belonged to clonal complex (CC) 230, sequence type (ST) 276. However, for the other strains, the DiversiLab® method cannot be used to predict to which ST a strain belongs. The DiversiLab® method allowed us to identify the clonal expansion of S. pneumoniae serotype 19A strains isolated from both children and adults in 2007 and 2009.

MALDI-TOF MS Andromas strategy for the routine identification of bacteria, mycobacteria, yeasts, Aspergillus spp. and positive blood cultures.

All organisms usually isolated in our laboratory are now routinely identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) using the Andromas software. The aim of this study was to describe the use of this strategy in a routine clinical microbiology laboratory. The microorganisms identified included bacteria, mycobacteria, yeasts and Aspergillus spp. isolated on solid media or extracted directly from blood cultures. MALDI-TOF MS was performed on 2665 bacteria isolated on solid media, corresponding to all bacteria isolated during this period except Escherichia coli grown on chromogenic media. All acquisitions were performed without extraction. After a single acquisition, 93.1% of bacteria grown on solid media were correctly identified. When the first acquisition was not contributory, a second acquisition was performed either the same day or the next day. After two acquisitions, the rate of bacteria identified increased to 99.2%. The failures reported on 21 strains were due to an unknown profile attributed to new species (9) or an insufficient quality of the spectrum (12). MALDI-TOF MS has been applied to 162 positive blood cultures. The identification rate was 91.4%. All mycobacteria isolated during this period (22) were correctly identified by MALDI-TOF MS without any extraction. For 96.3% and 92.2% of yeasts and Aspergillus spp., respectively, the identification was obtained with a single acquisition. After a second acquisition, the overall identification rate was 98.8% for yeasts (160/162) and 98.4% (63/64) for Aspergillus spp. In conclusion, the MALDI-TOF MS strategy used in this work allows a rapid and efficient identification of all microorganisms isolated routinely.

Epidemiology of Streptococcus pneumoniae in France before introduction of the PCV-13 vaccine.

The purpose of this article was to describe the serotype incidence and antibiotic susceptibility of Streptococcus pneumoniae strains isolated from adults and children with invasive disease (IPD) or acute otitis media (AOM) before introduction of the 13-valent pneumococcal vaccine. During 2009, 494 strains of S. pneumoniae isolated were collected. Complete serotyping by latex antisera and molecular methods was performed. The most frequent serotypes isolated from children with IPD were 1 (26.2%), 19A (25%) and 7F (14.3%). Serotype 19A was predominant (42.1%) in children ≤ 2 years, whereas serotype 1 was predominant (63.3%) after the age of 5. Serotype 19A was the most frequently isolated serotype from AOM (62.3%). In adults, serotypes responsible for IPD were 7F (19.4%), 19A (13.7%), 1 (8.4%) and 3 (7.5%). The serotype 19A was predominant in adults older than 65 years (19.1%). The emergence of serotype 12F was observed in adults. Between 2007 and 2009, the introduction of PCV-7 has resulted in a significant decrease of IPD caused by serotypes included in the vaccine, in children as well as in adults, confirming the herd effect. Serotype coverage of PCV-13 was 70% and 80.9% for adult and children's IPD, respectively. PCV-13 will be more efficient in preventing invasive diseases among children and adults.