Prescribers' experience and opinions on antimicrobial stewardship programmes in hospitals: a French nationwide survey.

OBJECTIVES: To assess prescribers' experiences and opinions regarding antimicrobial stewardship programme (ASP) activities. METHODS: A cross-sectional paper-based survey was conducted among prescribers in 27 out of 35 randomly selected large hospitals in France. RESULTS: All 27 investigated hospitals (20 non-university public, 4 university-affiliated and 3 private hospitals) had an ASP and an appointed antibiotic advisor (AA), with a median of 0.9 full-time equivalents per 1000 acute-care beds (IQR 0-1.4). Of the 1963 distributed questionnaires, 920 were completed (46.9%). Respondents were mainly attending physicians (658/918, 71.7%) and medical specialists (532/868, 61.3%). Prescribers identified two main ASP objectives: to limit the spread of resistance (710/913, 77.8%) and to improve patient care and prognosis (695/913, 76.1%). The presence of an AA constituted a core element of ASP (96.2% agreement between answers of ASP leader and respondents). Respondents acknowledged an AA's usefulness especially on therapeutic issues, i.e. choosing appropriate antibiotic (agreement 84.7%) or adapting treatment (89.6%), but less so on diagnostic issues (31.4%). Very few respondents reported unsolicited counselling and post-prescription controls. Three-quarters of prescribers identified local guidelines (692/918, 75.4%). Prescribers did not approve of measures counteracting their autonomy, i.e. automatic stop orders (agreement 23.4%) or pre-approval by AAs (28.8%). They agreed more with educational interventions (73.0%) and clinical staff meetings (70.0%). CONCLUSIONS: Prescribers perceived ASP mainly through its 'on-demand' counselling activities. They preferred measures that did not challenge their clinical autonomy. High levels of antibiotic consumption in French hospitals bring into question the effectiveness of such an approach. However, limited ASP staffing and resources may preclude extended activities.

No relationship between late HIV diagnosis and social deprivation in newly diagnosed patients in France.

OBJECTIVES: The aim of the study was to determine whether there is a relationship between social deprivation and time of HIV diagnosis in France. METHODS: Prospectively collected data from a multicentre database were used in the study. Patients with a first HIV diagnosis between 1 January 2014 and 31 December 2015 were selected from the database. Deprivation was measured using the European Deprivation Index (EDI), which is an ecological index constructed from the address of residence and based on the smallest geographical census unit, in which individuals are classified so as to be comparable with national quintiles. Time of diagnosis was classified as being at an early, intermediate, late, or advanced stage of disease. Age, gender, distance from home to HIV centre, most probable route of infection, and hepatitis B or C coinfection were considered in the analysis. Because of a strong interaction between gender and most probable route of infection, we constructed a 'population' variable: men who have sex with men (MSM), heterosexual men and women. RESULTS: Of 1421 newly diagnosed patients, 44% were diagnosed either late or at an advanced stage of disease, and 46.3% were in the highest deprivation quintile. Using multivariate logistic regression, 'population' [odds ratio (OR) 0.62 (95% confidence interval (CI) 0.48-0.78) for MSM compared with women] and age [OR 1.39 (95% CI 1.07-1.80), 1.72 (1.32-2.23) and 1.86 (1.40-2.47) for the second, third and fourth quartiles, respectively, compared with the first quartile] were found to be related to late diagnosis. EDI level was not related to late HIV diagnosis. CONCLUSIONS: 'Population' seems to be more relevant than EDI to define evidence-based interventions to limit late diagnosis.

Efficacy, safety and patient-reported outcomes of ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced individuals with hepatitis C virus genotype 1 and HIV coinfection with and without cirrhosis (ANRS HC31 SOFTRIH study).

OBJECTIVES: Studies evaluating the efficacy and safety of the fixed-dose combination ledipasvir (LDV)/sofosbuvir (SOF) in patients coinfected with HIV-1 and hepatitis C virus (HCV) have mainly included treatment-naïve patients without cirrhosis. We aimed to evaluate the efficacy and safety of this combination in treatment-experienced patients with and without cirrhosis. METHODS: We conducted a multicentre, open-label, double-arm, nonrandomized study in patients coinfected with HIV-1 and HCV genotype 1 with and without cirrhosis, who had good viral suppression on their antiretroviral regimens. All patients were pretreated with a first-generation NS3/4A protease inhibitor (PI) plus pegylated interferon/ribavirin. Patients received a fixed-dose combination of LDV/SOF for 12 weeks, or for 24 weeks if cirrhosis was present. The primary endpoint was a sustained virological response (SVR) 12 weeks after the end of therapy. Secondary endpoints included safety, pharmacokinetics and patient-reported outcomes. RESULTS: Of the 68 patients enrolled, 39.7% had cirrhosis. Sixty-five patients [95.6%; 95% confidence interval (CI): 87.6-99.1%; P < 0.0001] achieved an SVR, with similar rates of SVR in those with and without cirrhosis. Tolerance was satisfactory, with mainly grade 1 or 2 adverse events. Among patient-reported outcomes, only fatigue significantly decreased at the end of treatment compared with baseline [odds ratio (OR): 0.36; 95% CI: 0.14-0.96; P = 0.04]. Mean tenofovir area under the plasma concentration-time curve (AUC) at week 4 was high, with mean ± SD AUC variation between baseline and week 4 higher in cirrhotic than in noncirrhotic patients (3261.57 ± 1920.47 ng/mL vs. 1576.15 ± 911.97 ng/mL, respectively; P = 0.03). Mild proteinuria (54.4%), hypophosphataemia (50.0%), blood bicarbonate decrease (29.4%) and hypokalaemia (13.2%) were reported. The serum creatinine level was not modified. CONCLUSIONS: LDV/SOF provided a high SVR rate in PI-experienced subjects coinfected with HCV genotype 1 and HIV-1, including patients with cirrhosis.

Effectiveness and cost-effectiveness of interventions targeting harm reduction and chronic hepatitis C cascade of care in people who inject drugs: The case of France.

Direct-acting antivirals (DAAs) represent an opportunity to improve hepatitis C virus (HCV) care cascade. This combined with improved harm reduction interventions may lead to HCV elimination especially in people who inject drugs (PWID). We assessed the effectiveness/cost-effectiveness of improvements in harm reduction and chronic hepatitis C (CHC) care cascade in PWID in France. We used a dynamic model of HCV transmission and CHC natural history and evaluated the following: improved needle/syringe programmes-opioid substitution therapies, faster diagnosis/linkage to care, earlier treatment initiation, alone and in combination among active PWID (mean age = 36). Outcomes were as follows: life expectancy in discounted quality-adjusted life years (QALYs); direct lifetime discounted costs; incremental cost-effectiveness ratio (ICER); number of infections/reinfections. Under the current practice, life expectancy was 15.846 QALYs, for a mean lifetime cost of €20 762. Treatment initiation at F0 fibrosis stage alone was less effective and more costly than faster diagnosis/linkage to care combined with treatment initiation at F0, which increased life expectancy to 16.694 QALYs, decreased new infections by 37%, with a ICER = €5300/QALY. Combining these interventions with harm reduction improvements was the most effective scenario (life expectancy = 16.701 QALYs, 41% decrease in new infections) but was not cost-effective (ICER = €105 600/QALY); it became cost-effective with higher initial HCV incidence rates and lower harm reduction coverage than in our base-case scenario. This study illustrated the high effectiveness, and cost-effectiveness, of a faster diagnosis/linkage to care together with treatment from F0 with DAAs. This "Test and treat" strategy should play a central role both in improving the life expectancies of HCV-infected patients, and in reducing HCV transmission.

Hepatitis C: The beginning of the end-key elements for successful European and national strategies to eliminate HCV in Europe.

Hepatitis C virus (HCV) infection is a major public health problem in the European Union (EU). An estimated 5.6 million Europeans are chronically infected with a wide range of variation in prevalence across European Union countries. Although HCV continues to spread as a largely "silent pandemic," its elimination is made possible through the availability of the new antiviral drugs and the implementation of prevention practices. On 17 February 2016, the Hepatitis B & C Public Policy Association held the first EU HCV Policy Summit in Brussels. This summit was an historic event as it was the first high-level conference focusing on the elimination of HCV at the European Union level. The meeting brought together the main stakeholders in the field of HCV: clinicians, patient advocacy groups, representatives of key institutions and regional bodies from across European Union; it served as a platform for one of the most significant disease elimination campaigns in Europe and culminated in the presentation of the HCV Elimination Manifesto, calling for the elimination of HCV in Europe by 2030. The launch of the Elimination Manifesto provides a starting point for action in order to make HCV and its elimination in Europe an explicit public health priority, to ensure that patients, civil society groups and other relevant stakeholders will be directly involved in developing and implementing HCV elimination strategies, to pay particular attention to the links between hepatitis C and social marginalization and to introduce a European Hepatitis Awareness Week.

Disparities in HIV-1 transmitted drug resistance detected by ultradeep sequencing between men who have sex with men and heterosexual populations.

OBJECTIVES: Transmitted drug resistance (TDR) can impair the response to first-line antiretroviral therapy. In treatment-naïve patients chronically infected with HIV type 1 (HIV-1), it was previously shown through Sanger sequencing that TDR was more common in men who have sex with men (MSM) than in other transmission risk groups. We aimed to compare two HIV-1 transmission groups in terms of the presence of TDR mutations. METHODS: We investigated, through Sanger sequencing and ultradeep sequencing (UDS), the presence of resistance mutations, both in majority (> 20%) and in minority (1-20%) proportions, in 70 treatment-naïve MSM and 70 treatment-naïve heterosexual patients who recently screened positive for HIV-1. RESULTS: The global prevalence of TDR was not significantly different between the two groups, either by Sanger or by UDS. Nevertheless, a higher frequency of nucleoside reverse transcriptase inhibitor TDR was observed among heterosexual patients (P = 0.04). There was also a trend for a higher frequency of TDR among MSM infected with HIV-1 subtype B compared with MSM infected with HIV-1 non-B subtypes (P = 0.06). CONCLUSIONS: Ultradeep sequencing UDS allowed sensitive monitoring of TDR, and highlighted some disparities between transmission groups.

Strengthened Ebola surveillance in France during a major outbreak in West Africa: March 2014-January 2016.

Introduction An unprecedented outbreak of Ebola virus diseases (EVD) occurred in West Africa from March 2014 to January 2016. The French Institute for Public Health implemented strengthened surveillance to early identify any imported case and avoid secondary cases. METHODS: Febrile travellers returning from an affected country had to report to the national emergency healthcare hotline. Patients reporting at-risk exposures and fever during the 21st following day from the last at-risk exposure were defined as possible cases, hospitalised in isolation and tested by real-time polymerase chain reaction. Asymptomatic travellers reporting at-risk exposures were considered as contact and included in a follow-up protocol until the 21st day after the last at-risk exposure. RESULTS: From March 2014 to January 2016, 1087 patients were notified: 1053 were immediately excluded because they did not match the notification criteria or did not have at-risk exposures; 34 possible cases were tested and excluded following a reliable negative result. Two confirmed cases diagnosed in West Africa were evacuated to France under stringent isolation conditions. Patients returning from Guinea (n = 531; 49%) and Mali (n = 113; 10%) accounted for the highest number of notifications. CONCLUSION: No imported case of EVD was detected in France. We are confident that our surveillance system was able to classify patients properly during the outbreak period.

Cost-effectiveness and budget impact of interferon-free direct-acting antiviral-based regimens for hepatitis C treatment: the French case.

We evaluated the cost-effectiveness and the budget impact of new DAA-based regimen use in France. A Markov model simulated chronic hepatitis C (CHC) treatment interventions with IFN-based and IFN-free regimens at stage of fibrosis ≥F3, ≥F2 or regardless of fibrosis stage, and treatment either with the least or the most expensive combination. It estimated quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). It also assessed the budget impact over 5 years of treating all CHC-screened patients, regardless of fibrosis, assuming ≤20 000 patients treated/year and priority to ≥F3. Sensitivity analyses were also conducted. For genotypes (G) 1-4, the initiation of IFN-free regardless of fibrosis was a cost-effective strategy compared to prior standard of care (SOC) initiated at stage F2: €40 400-88 300/QALY gained in G1; similar results were obtained for patients infected with G4. Considering G2-3, the most cost-effective strategy was IFN-based regimens regardless of fibrosis compared to prior SOC initiated at stage F2: €21 300 and €19 400/QALY gained, respectively; the strategy with IFN-free regimens being more effective but not cost-effective at current costs. The budget impact of treating all CHC-screened patients over 5 years would range between 3.5 and 7.2 billion €, depending on whether one considers the least or the most expensive combination of new DAAs and whether one treats G2-3 with IFN-based or IFN-free new DAAs. In France, treatment initiation with new DDAs regardless of fibrosis stage is cost-effective, but would add 3.5-7.2 billion € to an already overburdened medical care system.

Characteristics and consequences of medical care interruptions in HIV-infected patients in France.

To describe the consequences of medical care interruptions (MCIs) we selected patients with at least two medical encounters between January 2006 and June 2013 in the Dat'AIDS cohort. Patients with any time interval >15 months between two visits were defined as having a MCI, as opposed to uninterrupted follow-up (UFU). Patients' characteristics at the time of HIV diagnosis and at the censoring date were compared between groups. Cox proportional hazards models were built to assess the role of interruptions on survival (total and AIDS-free). Of 11 116 patients, 824 had at least one MCI. These patients were younger at the time of HIV diagnosis (30 vs. 33 years, P < 0·0001). MCI was less frequent in men having sex with men vs. heterosexual patients [odds ratio (OR) 0·81, 95% confidence interval (CI) 0·69-0·96)], and a centre effect was described. MCI was independently associated with AIDS (OR 2·54, 95% CI 2·10-3·09) and death (OR 2·65, 95% CI 1·94-3·61). At the censoring date, 52·2% of patients with at least one MCI had viral load below detection vs. 85·3% of the UFU group (P < 0·0001). In conclusion, MCIs were associated with patients' survival and with the proportion of viral loads below detection in our cohort, compromising individual and collective treatment benefits.

Time to initiation of antiretroviral therapy in HIV-infected patients diagnosed with an opportunistic disease: a cohort study.

OBJECTIVES: The aim of the study was to identify factors associated with the time between opportunistic disease (OD) diagnosis and antiretroviral therapy (ART) initiation in HIV-infected patients presenting for care with an OD, and to evaluate the outcomes associated with any delay. METHODS: A multicentre cohort study was undertaken in London, Paris and Lille/Tourcoing. The medical records of patients diagnosed from 2002 to 2012 were reviewed. RESULTS: A total of 437 patients were enrolled in the study: 70% were male, the median age was 40 years, 42% were from sub-Saharan Africa, 68% were heterosexual, the median CD4 count was 40 cells/µL, and the most common ODs were Pneumocystis pneumonia (37%), tuberculosis (24%), toxoplasmosis (12%) and Kaposi's sarcoma (11%). Of these patients, 400 (92%) started ART within 24 weeks after HIV diagnosis, with a median time from OD diagnosis to ART initiation of 30 [interquartile range (IQR) 16-58] days. Patients diagnosed between 2009 and 2012 had a shorter time to ART initiation than those diagnosed in earlier years [hazard ratio (HR) 2.07; 95% confidence interval (CI) 1.58-2.72]. Factors associated with a longer time to ART initiation were a CD4 count ≥ 200 cells/µL (HR 0.30; 95% CI 0.20-0.44), tuberculosis (HR 0.40; 95% CI 0.30-0.55) and diagnosis in London (HR 0.62; 95% CI 0.48-0.80). Patients initiating 'deferred' ART (by ≥ 30 days) exhibited no difference in disease progression or immunovirological response compared with patients who had shorter times to ART initiation. Patients in the 'deferred' group were less likely to have ART modifications (HR 0.69; 95% CI 0.48-1.00) and had shorter in-patient stays (mean 14.2 days shorter; 95% CI 8.9-19.5 days) than patients in the group whose ART was not deferred. CONCLUSIONS: The time between OD diagnosis and ART initiation remains heterogeneous and relatively long, particularly in individuals with a high CD4 count or tuberculosis or those diagnosed in London. Deferring ART was associated with fewer ART modifications and shorter in-patient stays.

Dynamic modelling of hepatitis C virus transmission among people who inject drugs: a methodological review.

Equipment sharing among people who inject drugs (PWID) is a key risk factor in infection by hepatitis C virus (HCV). Both the effectiveness and cost-effectiveness of interventions aimed at reducing HCV transmission in this population (such as opioid substitution therapy, needle exchange programmes or improved treatment) are difficult to evaluate using field surveys. Ethical issues and complicated access to the PWID population make it difficult to gather epidemiological data. In this context, mathematical modelling of HCV transmission is a useful alternative for comparing the cost and effectiveness of various interventions. Several models have been developed in the past few years. They are often based on strong hypotheses concerning the population structure. This review presents compartmental and individual-based models to underline their strengths and limits in the context of HCV infection among PWID. The final section discusses the main results of the papers.

Quinolones versus macrolides in the treatment of legionellosis: a systematic review and meta-analysis.

BACKGROUND: Legionellosis is a life-threatening disease. The clinical superiority of quinolones or macrolides for treating patients with legionellosis has not been established. METHODS: We performed a systematic review and meta-analysis of studies reporting data that allowed the comparison of quinolones versus macrolides in the treatment of proven legionellosis published from 1 January 1985 to 31 January 2013. We collected baseline aggregate patient characteristics. Studied outcomes included mortality, clinical cure, time to apyrexia, length of hospital stay and occurrence of complications in each treatment group. Treatment effect was assessed using a Mantel-Haenszel random effects model. RESULTS: Among 1005 abstracts reviewed, 12 studies were selected (n=879 patients). No randomized controlled trial was performed directly comparing quinolone and macrolide efficacy in legionellosis. Mean age was 58.3 years, 27.7% were women and Fine score was ≥ 4 in 35.8%. Among 253 patients who received quinolone monotherapy, 10 died (4.0%). Among 211 patients who received macrolide monotherapy, 23 died (10.9%). The pooled OR of death for treatment with a quinolone versus a macrolide was 0.5 (95% CI 0.2-1.3, n=8 studies, 464 patients). Length of stay was significantly shorter in the quinolone monotherapy group. The difference was 3.0 days (95% CI 0.7-5.3, P=0.001, n=3 studies, 263 patients). Neither of two tests for heterogeneity was significant (I (2)=0% for both, P=1). Other studied outcomes were not significantly different among treatment groups. CONCLUSIONS: Few clinical data on legionellosis treatment are available. This first meta-analysis showed a trend toward a lower mortality rate and a significant decrease in length of hospital stay among patients receiving quinolones. These results must be confirmed by a randomized controlled trial.

Drug reaction with eosinophilia and systemic symptoms, or virus reactivation with eosinophilia and systemic symptoms as a manifestation of immune reconstitution inflammatory syndrome in a patient with HIV?

We report a case of drug reaction with eosinophilia and systemic symptoms (DRESS) in a patient with HIV receiving antitoxoplasmic drugs (adiazine and pyrimethamine) and levetiracetam along with highly active antiretroviral therapy (tenofovir-emtricitabine, darunavir and ritonavir). Cytomegalovirus (CMV) infection was reactivated in the 7 weeks before the development of DRESS but was successfully treated with ganciclovir and corticosteroids. DRESS flare was concomitant with another CMV reactivation after the withdrawal of ganciclovir. This case report is an example of DRESS that may be considered real DRESS or virus reactivation with eosinophilia and systemic symptoms (VRESS) as a manifestation of immune reconstitution inflammatory syndrome. The case confirms that herpesvirus reactivation precedes DRESS or VRESS, and suggests the need to monitor herpesvirus infection in patients at risk for the infection or after the initiation of culprit drugs.

Assessment of the Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic in the Middle East and risk of international spread using a novel maximum likelihood analysis approach.

The emergence of the novel Middle East (ME) respiratory syndrome coronavirus (MERS-CoV) has raised global public health concerns regarding the current situation and its future evolution. Here we propose an integrative maximum likelihood analysis of both cluster data in the ME and importations in a set of European countries to assess the transmission scenario and incidence of sporadic infections. Our approach is based on a spatial-transmission model integrating mobility data worldwide and allows for variations in the zoonotic/environmental transmission and under-ascertainment. Maximum likelihood estimates for the ME, considering outbreak data up to 31 August 2013, indicate the occurrence of a subcritical epidemic with a reproductive number R of 0.50 (95% confidence interval (CI): 0.30-0.77) associated with a daily rate of sporadic introductions psp of 0.28 (95% CI: 0.12-0.85). Infections in the ME appear to be mainly dominated by zoonotic/environmental transmissions, with possible under-ascertainment (ratio of estimated to observed (0.116) sporadic cases equal to 2.41, 95% CI: 1.03-7.32). No time evolution of the situation emerges. Analyses of flight passenger data from ME countries indicate areas at high risk of importation. While dismissing an immediate threat for global health security, this analysis provides a baseline scenario for future reference and updates, suggests reinforced surveillance to limit under-ascertainment, and calls for alertness in high importation risk areas worldwide.

Late dihydroartemisinin-piperaquine treatment failure of P. falciparum malaria attack related to insufficient dosing in an obese patient.

We report the case of an obese patient who experienced late failure on day28 of a well-conducted treatment with artesunate, followed by dihydroartemisinin-piperaquine (DHA-PPQ) for a severe P. falciparum malaria attack. The same P. falciparum strain was evidenced at day0 and day28. Genotypic and phenotypic resistance tests could not explain this treatment failure. The low plasma piperaquine concentration at failure may explain the poor elimination of residual parasites.

Efficacy of new antiretroviral drugs in treatment-experienced HIV-infected patients: a systematic review and meta-analysis of recent randomized controlled trials.

OBJECTIVES: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the overall efficacy of new antiretroviral drugs, as well as the factors associated with increased efficacy. We compared CD4 cell count increases associated with chemokine (C-C motif) receptor 5 (CCR5) inhibitors or other new drugs, using indirect comparison. METHODS: We included RCTs published in 2003-2010 that assessed the 48-week immunological and virological efficacy of adding new antiretroviral drugs vs. placebo to optimized background therapy (OBT) in treatment-experienced subjects. These drugs included maraviroc, vicriviroc, enfuvirtide, raltegravir, etravirine, tipranavir and darunavir. We collected baseline descriptive characteristics, CD4 cell count changes and virological suppression proportions (percentage with HIV RNA <50 HIV-1 RNA copies/mL). RESULTS: We identified 10 studies which included a total of 6401 patients. New drugs were associated with increased virological suppression (pooled odds ratio 2.97) and larger CD4 count increases (pooled nonstandardized difference 39 cells/µL) compared with placebo. OBT genotypic sensitivity scores (GSSs) were also associated with larger differences in virological suppression (P<0.001 for GSS=0,≤1 and ≤2) and CD4 cell count increase (GSS=0, P<0.001; GSS ≤1, P=0.002; GSS ≤2, P=0.015) between the two groups. CCR5 inhibitors were not associated with significant gains in CD4 cell counts (P=0.22) compared with other new drugs. CONCLUSIONS: Our study confirmed the overall immunological and virological efficacy of new antiretroviral drugs in treatment-experienced patients, compared with placebo. The main predictive factor for efficacy was the number of fully active drugs. CCR5 inhibitors did not increase CD4 cell count to a greater extent than other new drugs.

Outcome of patients with diabetes with negative percutaneous bone biopsy performed for suspicion of osteomyelitis of the foot.

AIMS: To assess the outcome of patients with diabetes with suspicion of osteomyelitis of the foot who had undergone a percutaneous bone biopsy that yielded negative microbiological results, with focus on the occurrence of osteomyelitis at the biopsied site. METHODS: Medical charts of adult patients with diabetes with a negative percutaneous bone biopsy were reviewed. Patients' outcome was evaluated at least 2 years after the initial bone biopsy according to wound healing, the results of a new bone biopsy and bone imaging evaluation when applicable. RESULTS: From January 2001 to January 2008, 41 patients with diabetes (30 men/11 women; mean age 58.1 ± 9.6 years; mean diabetes duration 15.8 ± 6.7 years) met study criteria. Osteomyelitis was suspected based on combined clinical and imaging diagnostic criteria. On follow-up at a mean duration of 41.2 ± 22.5 months post-bone biopsy, 16 patients had complete wound healing (39.0%). Of the 25 other patients, 15 had a new bone biopsy performed, six of which yielded positive microbiological results, and among the 10 patients who neither healed nor underwent bone biopsy, comparative radiography of the foot showed a stable aspect of the biopsied site in six of them, for whom the data were available. Finally, osteomyelitis of the foot at the site where the initial bone biopsy had been performed was confirmed during follow-up in six patients (14.6%) and was suspected in four additional patients (9.7%). CONCLUSIONS: The results of the present study suggest that, of patients with diabetes with the suspicion of osteomylelitis and a negative percutaneous bone biopsy, only one out of four will develop osteomyelitis within 2 years of the biopsy.

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.