Availability of drugs and resistance testing for BPaLM regimen for rifampicin-resistant tuberculosis in Europe.

OBJECTIVES: Multidrug-resistant/Rifampicin-resistant tuberculosis (TB) is a major obstacle to successful TB control. The recommendation by the World Health Organization to use bedaquiline, pretomanid, linezolid and moxifloxacin (BPaL(M)) for 6 months, based on results of three trials with high efficacy and low toxicity, has revolutionized treatment options. METHODS: In this study, representatives of the Tuberculosis Network European Trialsgroup (TBnet) in 44/54 countries of the WHO Europe region document the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September to November 2023. RESULTS: 24/44 (54.5%), 42/44 (95.5%), 43/44 (97.7%), and 43/44 (97.7%) had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23/44 (52.3%) had access to all the drugs composing the BPaL(M) regimen. 7/44 (15.9%), 28/44 (63.6%), 34/44 (77.3%) and 36/44 (81.8%) had access to DST for pretomanid, bedaquiline, linezolid and moxifloxacin, respectively. DST was available for all medicines composing the BPaL(M) regimen in 6/44 (13.6%) countries. CONCLUSION: Only in about half of the countries participating in the survey clinicians have access to all the BPaL(M) regimen drugs. In less than a fifth of countries, a complete DST is possible. Rapid scale up of DST capacity to prevent unnoticed spread of drug resistance and equal access to new regimens are urgently needed in Europe.

Towards clinical breakpoints for non-tuberculous mycobacteria - Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution.

OBJECTIVE: For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints. METHODS: We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TECOFFs) were determined by EUCAST methodology including quality control (QC) strains. RESULTS: The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For QC M. avium and M. peregrinum, ≥95% of MIC values were well within recommended QC ranges. CONCLUSION: As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs.

Import and transmission of Mycobacterium orygis and Mycobacterium africanum, Norway.

BACKGROUND: The aim of the current study was to improve our understanding of the origins and transmission of Mycobacterium africanum (MAF) in Norway. METHODS: Whole-genome sequences (WGS) were generated for all (n = 29) available clinical isolates received at the Norwegian National Reference Laboratory for Mycobacteria (NRL) and identified as MAF in Norway, in the period 2010-2020. Phylogenetic analyses were performed. RESULTS: The analyses indicated several imports of MAF lineage 6 from both East and West African countries, whereas MAF lineage 5 was restricted to patients with West African connections. We also find evidence for transmission of MAF in Norway. Finally, our analyses revealed that a group of isolates from patients originating in South Asia, identified as MAF by means of a commercial line-probe assay, in fact belonged to Mycobacterium orygis. CONCLUSIONS: Most MAF cases in Norway are the result of import, but transmission is occurring within Norway.

Non-tuberculous mycobacterial pulmonary infections. / Lungeinfeksjoner med ikke-tuberkuløse mykobakterier.

BAKGRUNN: Lungeinfeksjoner med ikke-tuberkuløse mykobakterier påvises jevnlig i klinisk praksis. Diagnostikk og behandling er utfordrende, og internasjonale retningslinjer bygger i stor grad på erfaring og kasuistikker. Temaet er kort og generelt omtalt i Tuberkuloseveilederen, utover det finnes ingen nasjonal behandlingsveileder om temaet. Denne artikkelen sammenfatter den nyeste kunnskapen om emnet, med hovedvekt på diagnostikk og behandling. KUNNSKAPSGRUNNLAG: Vi søkte i PubMed, Embase og Cochrane etter alle oversiktsartikler og systematiske oversiktsartikler i tidsrommet 2007-17 om ikke-tuberkuløse mykobakterier som årsak til lungesykdom. RESULTATER: Ved diagnostikk og behandling av lungeinfeksjoner med ikke-tuberkuløse mykobakterier må både kliniske, radiologiske og mikrobiologiske funn vurderes før man beslutter om det er behandlingsindikasjon. Identifikasjon av art og eventuell underart av påvist mykobakterie og resistensmønster er av stor betydning. Behandlingen består av en kombinasjon av flere medikamenter over lang tid som ofte har mange bivirkninger og interaksjoner. FORTOLKNING: Behandlingsresultatene for lungeinfeksjoner med ikke-tuberkuløse mykobakterier er varierende. Det er viktig å ta stilling til om nytten av behandlingen forventes å oppveie ulempene den kan medføre. For mange pasienter vil optimalisering av øvrig behandling for den underliggende lungesykdommen være viktigst. Pasientene må følges opp regelmessig med ekspektoratprøver og monitorering av bivirkninger.

Genome-based transmission modelling separates imported tuberculosis from recent transmission within an immigrant population.

In many countries the incidence of tuberculosis (TB) is low and is largely shaped by immigrant populations from high-burden countries. This is the case in Norway, where more than 80 % of TB cases are found among immigrants from high-incidence countries. A variable latent period, low rates of evolution and structured social networks make separating import from within-border transmission a major conundrum to TB control efforts in many low-incidence countries. Clinical Mycobacterium tuberculosis isolates belonging to an unusually large genotype cluster associated with people born in the Horn of Africa have been identified in Norway over the last two decades. We modelled transmission based on whole-genome sequence data to estimate infection times for individual patients. By contrasting these estimates with time of arrival in Norway, we estimate on a case-by-case basis whether patients were likely to have been infected before or after arrival. Independent import was responsible for the majority of cases, but we estimate that about one-quarter of the patients had contracted TB in Norway. This study illuminates the transmission dynamics within an immigrant community. Our approach is broadly applicable to many settings where TB control programmes can benefit from understanding when and where patients acquired TB.

Stratification by interferon-γ release assay level predicts risk of incident TB.

INTRODUCTION: Targeted testing and treatment of latent TB infection (LTBI) are priorities on the global health agenda, but LTBI management remains challenging. We aimed to evaluate the prognostic value of the QuantiFERON TB-Gold (QFT) test for incident TB, focusing on the interferon (IFN)-γ level, when applied in routine practice in a low TB incidence setting. METHODS: In this large population-based prospective cohort, we linked QFT results in Norway (1 January 2009-30 June 2014) with national registry data (Norwegian Surveillance System for Infectious Diseases, Norwegian Prescription Database, Norwegian Patient Registry and Statistics Norway) to assess the prognostic value of QFT for incident TB. Participants were followed until 30 June 2016. We used restricted cubic splines to model non-linear relationships between IFN-γ levels and TB, and applied these findings to a competing risk model. RESULTS: The prospective analyses included 50 389 QFT results from 44 875 individuals, of whom 257 developed TB. Overall, 22% (n=9878) of QFT results were positive. TB risk increased with the IFN-γ level until a plateau level, above which further increase was not associated with additional prognostic information. The HRs for TB were 8.8 (95% CI 4.7 to 16.5), 19.2 (95% CI 11.6 to 31.6) and 31.3 (95% CI 19.8 to 49.5) times higher with IFN-γ levels of 0.35 to <1.00, 1.00 to <4.00 and >4.00 IU/mL, respectively, compared with negative tests (<0.35 IU/mL). CONCLUSIONS: Consistently, QFT demonstrates increased risk of incident TB with rising IFN-γ concentrations, indicating that IFN-γ levels may be used to guide targeted treatment of LTBI.

Tuberculosis Outbreak in an Educational Institution in Norway.

Within 1 week in April 2013, three cases of pulmonary tuberculosis (TB) were reported among students attending training sessions at an educational institution in Oslo, Norway. By the end of October 2013, a total of nine epidemiologically linked cases had been reported. The outbreak encompassed a total of 24 cases from 2009 to 2014, among which all of the 22 Mycobacterium tuberculosis isolates available had identical mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) profiles (MtbC15-9 code 10287-189) belonging to the Beijing lineage. Whole-genome sequencing (WGS) of the M. tuberculosis isolates revealed 20 variable nucleotide positions within the cluster, indicating a clonal outbreak. The most likely index case was identified and diagnosed in Norway in 2009 but was born in Asia. WGS analyses verified that all of the cases were indeed part of a single transmission chain. However, even when combining WGS and intensified contact tracing, we were unable to fully reconstruct the TB transmission events.

Armed conflict and population displacement as drivers of the evolution and dispersal of Mycobacterium tuberculosis.

The "Beijing" Mycobacterium tuberculosis (Mtb) lineage 2 (L2) is spreading globally and has been associated with accelerated disease progression and increased antibiotic resistance. Here we performed a phylodynamic reconstruction of one of the L2 sublineages, the central Asian clade (CAC), which has recently spread to western Europe. We find that recent historical events have contributed to the evolution and dispersal of the CAC. Our timing estimates indicate that the clade was likely introduced to Afghanistan during the 1979-1989 Soviet-Afghan war and spread further after population displacement in the wake of the American invasion in 2001. We also find that drug resistance mutations accumulated on a massive scale in Mtb isolates from former Soviet republics after the fall of the Soviet Union, a pattern that was not observed in CAC isolates from Afghanistan. Our results underscore the detrimental effects of political instability and population displacement on tuberculosis control and demonstrate the power of phylodynamic methods in exploring bacterial evolution in space and time.

Evolution of extensively drug-resistant Mycobacterium tuberculosis from a susceptible ancestor in a single patient.

BACKGROUND: Mycobacterium tuberculosis is characterized by a low mutation rate and a lack of genetic recombination. Yet, the rise of extensively resistant strains paints a picture of a microbe with an impressive adaptive potential. Here we describe the first documented case of extensively drug-resistant tuberculosis evolved from a susceptible ancestor within a single patient. RESULTS: Genome sequences of nine serial M. tuberculosis isolates from the same patient uncovered a dramatic turnover of competing lineages driven by the emergence, and subsequent fixation or loss of single nucleotide polymorphisms. For most drugs, resistance arose through independent emergence of mutations in more than one clone, of which only one ultimately prevailed as the clone carrying it expanded, displacing the other clones in the process. The vast majority of mutations identified over 3.5 years were either involved in drug resistance or hitchhiking in the genetic background of these. Additionally, RNA-sequencing of isolates grown in the absence of drug challenge revealed that the efflux-associated iniBAC operon was up-regulated over time, whereas down-regulated genes include those involved in mycolic acid synthesis. CONCLUSIONS: We observed both rapid acquisitions of resistance to antimicrobial compounds mediated by individual mutations as well as a gradual increase in fitness in the presence of antibiotics, likely driven by stable gene expression reprogramming. The rapid turnover of resistance mutations and hitchhiking neutral mutations has major implications for inferring tuberculosis transmission events in situations where drug resistance evolves within transmission chains.

Two Norwegian patients with melioidosis presenting with bacteraemia and splenic and prostatic abscesses.

Infections caused by Burkholderia pseudomallei are rare in nonendemic areas, such as Scandinavia. We report the first two cases of melioidosis in Norway presenting with bacteraemia and splenic and prostatic abscesses, respectively.

Diphtheria outbreak in Norway: lessons learned.

We describe an outbreak of diphtheria in Norway that occurred in 2008 and affected 3 unvaccinated family members. The epidemic caught the public health system off-guard on most levels; the diagnosis was distrusted due to its rarity, no diphtheria anti-toxin was available, and notification procedures were not rigorously followed.

Tuberculosis among children in Oslo, Norway, from 1998 to 2009.

We investigated all confirmed cases of tuberculosis (TB) among children (age < 16 y) in Oslo from 1998 to 2009. The overall incidence rate was 2.6 per 100,000 person-y. All 24 children diagnosed with TB were of non-Western origin, and the overall incidence rate in this group was 8.1 per 100,000 person-y. Among children of Somali origin, the incidence rate was 52.5 per 100,000 person-y. Pulmonary infiltrates (n = 7), hilar lymphadenopathy without infiltrates (n = 7) and lymph node TB in the neck (n = 5) were the most common clinical presentations. However, we also diagnosed TB meningitis, spondylitis, coxitis and pleuritis. None of the children were HIV-infected. Mycobacterium tuberculosis was cultivated in 19 out of 24 cases (79%). Of the 19 culture-positive cases, 13 had been tested with a polymerase chain reaction, of which 7 (54%) were positive. Isolates from 2 patients were resistant to isoniazid, 1 isolate was resistant to streptomycin, and 2 were resistant to both isoniazid and streptomycin. All children were treated according to a directly observed treatment short-course (DOTS) protocol. One child with TB meningitis died. Twenty-one patients finished treatment in Oslo, and all were cured without major sequelae or recurrence. TB among non-Western immigrant children is still a challenge in Norway.