Extrapulmonary Mycobacterium abscessus Infections, France, 2012-20201.

Mycobacterium abscessus infection is challenging to treat. Extrapulmonary M. abscessus infections (EP-MAB) are less common than pulmonary M. abscessus infections. To evaluate treatment regimens, we retrospectively analyzed consecutive microbiologically confirmed EP-MAB cases diagnosed in France during 2012-2020. We studied 45 patients with EP-MAB, including 14 bone and joint infections, 10 skin and soft tissue infections, and 8 lymph node infections. Most (62%) patients had no reported immunodeficiency. In 27 patients, EP-MAB followed healthcare-associated (44%) or environmental (16%) injuries. Of the 45 isolates, 25 were subspecies abscessus, 10 bolletii, and 9 massiliense; 1 was unidentified. Cure was achieved for 36 (80%) patients who received a median antimicrobial regimen of 6 months; 22 (55%) also underwent surgery. Four patients died, and 5 were unavailable for follow-up. EP-MAB predominantly affects immunocompetent patients after an injury; outcomes are favorable. We propose a >6-month regimen of antimicrobial therapy with consideration for surgery and regular patient reassessment.

Association of Healthcare and Aesthetic Procedures with Infections Caused by Nontuberculous Mycobacteria, France, 2012‒2020.

We describe nontuberculous mycobacteria (NTM) infections during 2012-2020 associated with health care and aesthetic procedures in France. We obtained epidemiologic data from the national early warning response system for healtcare-associated infections and data on NTM isolates from the National Reference Center for Mycobacteria. We compared clinical and environmental isolates by using whole-genome sequencing. The 85 original cases were reported after surgery (48, 56%), other invasive procedures (28, 33%) and other procedures (9, 11%). NTM isolates belonged to rapidly growing (73, 86%) and slowly growing (10, 12%) species; in 2 cases, the species was not identified. We performed environmental investigations for 38 (45%) cases; results for 12 (32%) were positive for the same NTM species as for the infection. In 10 cases that had environmental and clinical samples whose genomes were similar, the infection source was probably the water used in the procedures. NTM infections could be preventable by using sterile water in all invasive procedures.

Seasonal variations in blood culture numbers and time to positivity and potential impact of reducing incubation periods.

Patients with viral respiratory infections often present symptoms compatible with bloodstream infections. Consequently, the winter period commonly associated with epidemic respiratory illnesses shows an increase in the number of blood cultures (BC) and to occasional saturation of automated BC systems. Here, we explored the seasonal variations in BC samples and the potential impact of shortening the incubation time of BC when automated BC systems are close to saturation. A retrospective study was conducted during a 3-year period in 4 hospitals located in the Paris region, France. All aerobic and anaerobic bottles were included, except pediatric bottles and those sampled for suspicion of endocarditis. The number of BC bottles collected during the winter period was compared to the annual baseline. All bottles positive after a 4-day incubation were analyzed regarding clinical and microbiological findings. The number of BC bottles was significantly higher during the winter periods, compared to the annual baseline (up to 14%). A total of 292,349 BC bottles were analyzed with 23,363 (8.0%) positive, including 236 (1%) after a 4-day incubation. Of these 236 bottles, 76 (64.8%) were positive with a contaminant, 78 (33.1%) with a clinically significant microorganism identified for the same patient in the previous 4 days, and only 5 (2.1%) with a clinically significant microorganism not previously identified. Winter periods were associated with a significant increase in BC samples. Shortening the incubation time of BC bottles from 5 to 4 days seems a relevant option when automated BC systems are close to saturation.

Management of patients with pulmonary mycobacteriosis in France: a multicenter retrospective cohort study.

BACKGROUND: Recent studies report very low adherence of practitioners to ATS/IDSA recommendations for the treatment of nontuberculous mycobacteria pulmonary disease (NTM-PD), as well as a great variability of practices. Type of management could impact prognosis. METHODS: To evaluate management and prognosis of patients with NTM-PD cases with respect to ATS recommendations, we conducted a multicenter retrospective cohort study (18 sentinel sites distributed throughout France), over a period of six years. We collected clinical, radiological, microbiological characteristics, management and outcome of the patients (especially death or not). RESULTS: 477 patients with NTM-PD were included. Respiratory comorbidities were found in 68% of cases, tuberculosis sequelae in 31.4% of patients, and immunosuppression in 16.8% of cases. The three most common NTM species were Mycobacterium avium complex (60%), M. xenopi (20%) and M. kansasii (5.7%). Smear-positive was found in one third of NTM-PD. Nodulobronchiectatic forms were observed in 54.3% of cases, and cavitary forms in 19.1% of patients. Sixty-three percent of patients were treated, 72.4% of patients with smear-positive samples, and 57.5% of patients with smear-negative samples. Treatment was in adequacy with ATS guidelines in 73.5%. The 2-year mortality was 14.4%. In the Cox regression, treatment (HR = 0.51), age (HR = 1.02), and M. abscessus (3.19) appeared as the 3 significant independent prognostic factors. CONCLUSION: These findings highlight the adequacy between French practices and the ATS/IDSA guidelines. Treatment was associated with a better survival.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.

Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC).

Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.

Phenotypic and genotypic quinolone resistance in Escherichia coli underlining GyrA83/87 mutations as a target to detect ciprofloxacin resistance.

BACKGROUND: Quinolone resistance (QR) is one component of the MDR emerging in Escherichia coli and is of particular concern given the widespread use of fluoroquinolones. OBJECTIVES: To characterize the QR phenotypes and genotypes in E. coli responsible for bloodstream infections and to propose molecular determinants that could be targeted to predict ciprofloxacin resistance. METHODS: E. coli isolates from blood cultures in three French hospitals were studied for quinolone MICs and characterization of genotypic QR determinants (QRg). RESULTS: Among 507 isolates tested for MICs, 148 (29.2%) were resistant to quinolones based on EUCAST breakpoints and 143 (28.2%) harboured at least one QRg. QRg were mainly mutations in the QRDR (138 isolates, 27.2%), with 55.8% of these isolates carrying at least three QRDR mutations. gyrA mutations predominated (92.8%) followed by parC (61.6%), parE (32.6%) and gyrB (1.4%) mutations. Only 4.7% of the isolates harboured a plasmid-mediated quinolone resistance (PMQR) gene: aac(6')-Ib-cr (60.0%) or qnr (qnrS, qnrB) (32.0%). For the first time in France, we reported the qepA4 allele of the plasmid-encoded efflux pump QepA. Only five isolates carried PMQR without a QRDR mutation. The positive predictive value (PPV) for ciprofloxacin resistance was 100% for any QRg and 99.2% for gyrA mutations specifically. CONCLUSIONS: QR observed in E. coli isolates involved in bloodstream infections is still mainly due to QRDR mutations, especially at codons GyrA83/87, which could be used as a molecular target to rapidly detect resistance.

Genomic characterization of 16S rRNA methyltransferase-producing Escherichia coli isolates from the Parisian area, France.

BACKGROUND: The resistance to all aminoglycosides (AGs) conferred by 16S rRNA methyltransferase enzymes (16S-RMTases) is a major public health concern. OBJECTIVES: To characterize the resistance genotype, its genetic environment and plasmid support, and the phylogenetic relatedness of 16S-RMTase-producing Escherichia coli from France. METHODS: We screened 137 E. coli isolates resistant to all clinically relevant AGs from nine Parisian hospitals for 16S-RMTases. WGS was performed on clinical isolates with high-level AG resistance (MIC ≥256 mg/L) and their transformants. RESULTS: Thirty of the 137 AG-resistant E. coli produced 16S-RMTases: 11 ArmA, 18 RmtB and 1 RmtC. The 16S-RMTase producers were also resistant to third-generation cephalosporins (90% due to a blaCTX-M gene), co-trimoxazole, fluoroquinolones and carbapenems (blaNDM and blaVIM genes) in 97%, 83%, 70% and 10% of cases, respectively. Phylogenomic diversity was high in ArmA producers, with 10 different STs, but a similar genetic environment, with the Tn1548 transposon carried by a plasmid closely related to pCTX-M-3 in 6/11 isolates. Conversely, RmtB producers belonged to 12 STs, the most frequent being ST405 and ST complex (STc) 10 (four and four isolates, respectively). The rmtB gene was carried by IncF plasmids in 10 isolates and was found in different genetic environments. The rmtC gene was carried by the pNDM-US plasmid. CONCLUSIONS: ArmA and RmtB are the predominant 16S-RMTases in France, but their spread follows two different patterns: (i) dissemination of a conserved genetic support carrying armA in E. coli with high levels of genomic diversity; and (ii) various genetic environments surrounding rmtB in clonally related E. coli.

Current mentorship practices in the training of the next generation of clinical microbiology and infectious disease specialists: an international cross-sectional survey.

The purpose of this study was to describe the current practice of mentorship in clinical microbiology (CM) and infectious diseases (ID) training, to identify possible areas for improvement and to assess the factors that are associated with satisfactory mentorship. An international cross-sectional survey containing 35 questions was answered by 317 trainees or specialists who recently completed clinical training. Overall, 179/317 (56%) trainees were satisfied with their mentors, ranging from 7/9 (78%) in non-European countries, 39/53 (74%) in Northern Europe, 13/22 (59%) in Eastern Europe, 61/110 (56%) in Western Europe, 37/76 (49%) in South-Western Europe to 22/47 (47%) in South-Eastern Europe. However, only 115/317 (36%) respondents stated that they were assigned an official mentor during their training. In multivariable logistic regression analysis, the satisfaction of trainees was significantly associated with having a mentor who was a career model (OR 6.4, 95%CI 3.5-11.7), gave constructive feedback on work performance (OR 3.3, 95%CI 1.8-6.2), and knew the family structure of the mentee (OR 5.5, 95%CI 3.0-10.1). If trainees felt overburdened, 70/317 (22%) felt that they could not talk to their mentors. Moreover, 67/317 (21%) stated that they could not talk to their mentor when unfairly treated and 59/317 (19%) felt uncertain. Training boards and authorities responsible for developing and monitoring CM&ID training programmes should invest in the development of high-quality mentorship programmes for trainees in order to contribute to the careers of the next generation of professionals.

Native joint septic arthritis due to Clostridium tarantellae.

Clostridium is a diverse genus including more than 200 species involved in varied clinical presentations in infectious diseases. Septic arthritis caused by Clostridium sp. are however uncommon. We report here the first septic arthritis due to Clostridium tarantellae, formerly called Eubacterium tarantellae, in a patient under anti-TNF therapy.

Use of Andromas and Bruker MALDI-TOF MS in the identification of Neisseria.

Through the past decade, MALDI-TOF MS has been recognized as a fast and robust tool for identification of most bacteria in clinical microbiology. However, the accuracy of this method to identify Neisseria species is still debated, and few data are available about commensal Neisseria species identification. In this study, we assessed two MALDI-TOF MS systems (Bruker Biotyper and Andromas) for the identification of 88, 18, and 29 isolates of Neisseria gonorrhoeae, Neisseria meningitidis, and commensal Neisseria species, respectively. All 88 isolates of N. gonorrhoeae were correctly identified using both systems, and most N. meningitidis and commensal Neisseria species were well identified: only 1/18 isolates of N. meningitidis was misidentified using Bruker Biotyper, and 1 isolate of Neisseria polysaccharea was misidentified as N. meningitidis using both systems. These results strengthen the possibility to use MALDI-TOF MS as a single method for Neisseria identification in routine, with excellent performance for N. gonorrhoeae identification. However, results should be interpreted prudently for N. meningitdis and commensal Neisseria species when isolated from genital and oropharyngeal samples where these both species can coexist.

An enhanced regimen as post-exposure chemoprophylaxis for leprosy: PEP+.

The ongoing transmission of Mycobacterium (M.) leprae reflected in a very slow decline in leprosy incidence, forces us to be innovative and conduct cutting-edge research. Single dose rifampicin (SDR) as post-exposure prophylaxis (PEP) for contacts of leprosy patients, reduces their risk to develop leprosy by 60%. This is a promising new preventive measure that can be integrated into routine leprosy control programmes, as is being demonstrated in the Leprosy Post-Exposure Programme that is currently ongoing in eight countries.The limited (60%) effectiveness of SDR is likely due to the fact that some contacts have a preclinical infection beyond the early stages for which SDR is not sufficient to prevent the development of clinical signs and symptoms of leprosy. An enhanced regimen, more potent against a higher load of leprosy bacteria, would increase the effectiveness of this preventive measure significantly.The Netherlands Leprosy Relief (NLR) is developing a multi-country study aiming to show that breaking the chain of transmission of M. leprae is possible, evidenced by a dramatic reduction in incidence. In this study the assessment of the effectiveness of an enhanced prophylactic regimen for leprosy is an important component. To define the so called PEP++ regimen for this intervention study, NLR convened an Expert Meeting that was attended by clinical leprologists, public health experts, pharmacologists, dermatologists and microbiologists.The Expert Meeting advised on combinations of available drugs, with known efficacy against leprosy, as well as on the duration of the intake, aiming at a risk reduction of 80-90%. To come to a conclusion the Expert Meeting considered the bactericidal, sterilising and bacteriostatic activity of the potential drugs. The criteria used to determine an optimal enhanced regimen were: effectiveness, safety, acceptability, availability, affordability, feasibility and not inducing drug resistance.The Expert Meeting concluded that the enhanced regimen for the PEP++ study should comprise three standard doses of rifampicin 600 mg (weight adjusted when given to children) plus moxifloxacin 400 mg given at four-weekly intervals. For children and for adults with contraindications for moxifloxacin, moxifloxacin should be replaced by clarithromycin 300 mg (weight adjusted).

Selection of Resistance to Clarithromycin in Mycobacterium abscessus Subspecies.

Mycobacterium abscessus is an emerging pathogen against which clarithromycin is the main drug used. Clinical failures are commonly observed and were first attributed to acquired mutations in rrl encoding 23S rRNA but were then attributed to the intrinsic production of the erm(41) 23S RNA methylase. Since strains of M. abscessus were recently distributed into subspecies and erm(41) sequevars, we investigated acquired clarithromycin resistance mechanisms in mutants selected in vitro from four representative strains. Mutants were sequenced for rrl, erm(41), whiB, rpIV, and rplD and studied for seven antibiotic MICs. For mutants obtained from strain M. abscessus subsp. abscessus erm(41) T28 sequevar and strain M. abscessus subsp. bolletii, which are both known to produce effective methylase, rrl was mutated in only 19% (4/21) and 32.5% (13/40) of mutants, respectively, at position 2058 (A2058C, A2058G) or position 2059 (A2059C, A2059G). No mutations were observed in any of the other genes studied, and resistance to other antibiotics (amikacin, cefoxitin, imipenem, tigecycline, linezolid, and ciprofloxacin) was mainly unchanged. For M. abscessus subsp. abscessus erm(41) C28 sequevar and M. abscessus subsp. massiliense, not producing effective methylase, 100% (26/26) and 97.5% (39/40) of mutants had rrl mutations at position 2058 (A2058C, A2058G, A2058T) or position 2059 (A2059C, A2059G). The remaining M. abscessus subsp. massiliense mutant showed an 18-bp repeat insertion in rpIV, encoding the L22 protein. Our results showed that acquisition of clarithromycin resistance is 100% mediated by structural 50S ribosomal subunit mutations for M. abscessus subsp. abscessus erm(41) C28 and M. abscessus subsp. massiliense, whereas it is less common for M. abscessus subsp. abscessus erm(41) T28 sequevar and M. abscessus subsp. bolletii, where other mechanisms may be responsible for failure.

Comparison of Saramis 4.12 and IVD 3.0 Vitek MS Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Mycobacteria from Solid and Liquid Culture Media.

During the last decade, many investigators have studied matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for identification of mycobacteria. Diverse and contradictory results indicated that optimal level for routine testing has not been reached yet. This work aimed to assess Vitek MS through two distinct versions, Saramis v4.12 RUO and the IVD v3.0, under conditions close to routine laboratory practice. Overall, 111 mycobacterial isolates were subjected to protein extraction and same spectra were matched against both databases. The IVD v3.0 database proved to be superior to Saramis v4.12 and its identification rates remarkably increased, from 67% to 94% for isolates grown on Middlebrook 7H10 solid medium and from 62% to 91% for isolates grown on mycobacterial growth indicator tube (MGIT) liquid medium. With this new version, IVD v3.0, MALDI-TOF MS might be integrated into routine clinical diagnostics, although molecular techniques remain mandatory in some cases.

Evaluation of the new GenoType NTM-DR kit for the molecular detection of antimicrobial resistance in non-tuberculous mycobacteria.

Objectives: Non-tuberculous mycobacteria (NTM) are emerging pathogens causing difficult-to-treat infections. We tested a new assay (GenoType NTM-DR) that detects natural and acquired resistance mechanisms to macrolides and aminoglycosides in frequently isolated NTM species. Methods: Performance was assessed on 102 isolates including reference strains [16 Mycobacterium avium , 10 Mycobacterium intracellulare , 8 Mycobacterium chimaera , 15 Mycobacterium chelonae and 53 Mycobacterium abscessus (including subsp. abscessus isolates, 18 with a t28 in erm(41) and 10 with a c28, 13 subsp. bolletii isolates and 12 subsp. massiliense isolates)]. Genotypes were determined by PCR sequencing of erm(41) and rrl for clarithromycin resistance and of the 1400-1480 rrs region for aminoglycoside resistance. Phenotypes were determined by MIC microdilution. Results: GenoType NTM-DR yielded results concordant with Sanger sequencing for 100/102 (98%) isolates. The erm(41) genotypic pattern was accurately identified for M. abscessus isolates . Mutations in rrl were detected in 15 isolates (7 M. avium complex, 5 M. abscessus and 3 M. chelonae ) with acquired clarithromycin resistance harbouring rrl mutations (a2057c, a2058g, a2058t or a2059c). Mutations in rrs were detected in five isolates with amikacin resistance harbouring the rrs mutation a1408g. In two isolates, the NTM-DR test revealed an rrl mutation (initial sequencing being WT), which was confirmed by re-sequencing. The test results were concordant with phenotypic susceptibility testing in 96/102 (94.1%) isolates, with four clarithromycin-resistant and two amikacin-resistant isolates not harbouring mutations. Conclusions: The GenoType NTM-DR test is efficient in detecting mutations predictive of antimicrobial resistance in M. avium complex, M. abscessus and M. chelonae.