Anna Cristina C. Carvalho

Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence. This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking. TBNET consensus statement on the management of patients with MDR/XDR-TB has been released in the Eur Respir J http://ow.ly/uizRD

TMC207: the first compound of a new class of potent anti-tuberculosis drugs

Disease caused by Mycobacterium tuberculosis continues as a global epidemic: over 2 billion people harbor latent TB infection, and more than 9 million new TB cases, of whom 500,000 are multidrug-resistant (MDR), and nearly 2 million deaths are estimated to occur each year. New drugs are required to shorten treatment duration of drug-sensitive TB and for the treatment of MDR-TB. TMC207 is a first-in-class diarylquinoline compound with a novel mechanism of action, the inhibition of bacterial ATP synthase, and potent activity against drug-sensitive and drug-resistant TB. It has bactericidal and sterilizing activity against M. tuberculosis and other mycobacterial species, but little activity against other bacteria. In a Phase II efficacy study conducted in patients with MDR-TB taking TMC207 plus a standard background regimen, the drug appeared to be safe and well tolerated, and showed significant efficacy after 2 months of treatment with conversion rates of sputum culture of 48% (vs 9% in the placebo group). Given the product development partnership between Tibotec and the TB Alliance, the strategies of using TMC207 in shorter first-line regimens or using it in second-line regimens for drug-resistant M. tuberculosis infections are both being pursued. No clinical data of TMC207 in TB patients with HIV coinfection have been published; drug-drug interaction studies with antiretrovirals are being conducted. Finally, the remarkable sterilizing capacity of TMC207 also makes it an attractive drug in the strategy of TB elimination. Current and future studies will determine the role of TMC207 in a shortened treatment regimen for drug-sensitive TB, a more effective and better-tolerated regimen for MDR-TB, the treatment of latent TB infection, and intermittent-TB treatment regimens.

Extensively drug-resistant tuberculosis: epidemiology and management.

The advent of antibiotics for the treatment of tuberculosis (TB) represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR) strains (ie, strains resistant to both isoniazid and rifampicin) has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB). The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR-TB.

Multiple-Dose Pharmacokinetics of Efavirenz with and without the Use of Rifampicin in HIV-Positive Patients

Rifampicin (RIF) decreases serum concentrations of several antiretroviral drugs. We carried out a prospective, comparative study to define efavirenz (EFV) pharmacokinetics in 16 cases and 13 controls. Cases were HIV and tuberculosis (TB) co-infected adults assuming RIF 600 mg once daily and EFV 800 mg once daily. Patients on EFV at standard 600 mg dose without RIF were taken as controls. EFV levels in plasma were assayed by high-performance liquid chromatography (HLPC) predose (C(trough)) and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 18, 22 and 24 hours post-dose, and pharmacokinetic parameters were determined by non-compartmental methods. Among cases, 81% were males, mean age was 37 years, 50% were Caucasians, mean weight was 64 kg, mean CD4 cell counts and log HIV RNA copies were 160/microl and 5.2 /microl, respectively. Cases had a significantly higher Cl/F/kg if compared with controls (0.269 +/- 0.12 versus 0.167 + 0.05 L/h/kg, p<0.01). Otherwise, dose-dependent pharmacokinetic parameters of EFV were similar between cases and controls. Interindividual variability was consistently higher among TB cases compared to controls for all considered parameters. All cases completed combined treatment and no increased EFV toxicity was observed. These results suggest that a dose of 800 mg of EFV in association with rifampicin may be appropriate for patients of weight > 60 kg in Europe. Therapeutic drug monitoring may be beneficial for patients on combination therapy with RIF.

Travel-associated sexually transmitted infections: an observational cross-sectional study of the GeoSentinel surveillance database

BACKGROUND Travel is thought to be a risk factor for the acquisition of sexually transmitted infections (STIs), but no multicentre analyses have been done. We aimed to describe the range of diseases and the demographic and geographical factors associated with the acquisition of travel-related STIs through analysis of the data gathered by GeoSentinel travel medicine clinics worldwide. METHODS We gathered data from ill travellers visiting GeoSentinel clinics worldwide between June 1, 1996, and Nov 30, 2010, and analysed them to identify STIs in three clinical settings: after travel, during travel, or immigration travel. We calculated proportionate morbidity for each of the three traveller groups and did logistic regression to assess the association between STIs and demographic, geographical, and travel variables. FINDINGS Our final analysis was of 112 180 ill travellers-64 335 patients seen after travel, 38 287 patients seen during travel, and 9558 immigrant patients. 974 patients (0·9%) had diagnoses of STIs, and 1001 STIs were diagnosed. The proportionate STI morbidities were 6·6, 10·2, and 16·8 per 1000 travellers in the three groups, respectively. STIs varied substantially according to the traveller category. The most common STI diagnoses were non-gonococcal or unspecified urethritis (30·2%) and acute HIV infection (27·6%) in patients seen after travel; non-gonococcal or unspecified urethritis (21·1%), epididymitis (15·2%), and cervicitis (12·3%) in patients seen during travel; and syphilis in immigrant travellers (67·8%). In ill travellers seen after travel, significant associations were noted between diagnosis of STIs and male sex, travelling to visit friends or relatives, travel duration of less than 1 month, and not having pretravel health consultations. INTERPRETATION The range of STIs varies substantially according to traveller category. STI preventive strategies should be particularly targeted at men and travellers visiting friends or relatives. Our data suggest target groups for pretravel interventions and should assist in post-travel screening and decision making. FUNDING US Centers for Disease Control and Prevention, and International Society of Travel Medicine.

Paradoxical Reaction during Tuberculosis Treatment in HIV-Seronegative Patients

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Chlamydia trachomatis genital infection in migrant female sex workers in Italy

We have assessed prevalence, incidence, and factors associated with increased risk for Chlamydia trachomatis genital infection among female migrant sex workers in Italy. In a prospective, observational study, women were offered free screening for sexually transmitted diseases and C. trachomatis was tested by a commercial ligase chain reaction assay in endocervical specimens. Of the 101 women tested, 14 (14%) were positive. The odds ratio (OR) for C. trachomatis infection was significantly higher for females under 24 years (OR = 4.31), women from Eastern Europe (OR = 4.80), and migrants less than 12 months in Italy (OR = 4.41). In a multivariate logistic regression model, only origin from Eastern Europe remained independently associated to a higher risk for C. trachomatis infection (OR = 6.05). This study provides evidence for high prevalence and incidence of C. trachomatis genital infection in migrant sex workers. Women from Eastern Europe have a significantly higher risk. These data reinforce the need for targeted control interventions.

Completion of screening for latent tuberculosis infection among immigrants

The objective of our study was to evaluate the sociodemographic factors associated with completion of screening for latent tuberculosis infection (LTBI) among undocumented immigrants in Brescia, Italy. Screening for LTBI was offered to 649 immigrants; 213 (33%) immigrants completed the first step of screening; only 44% (55/124) of individuals with a positive tuberculin skin test result started treatment for LTBI. The univariate analysis showed that being unmarried, of Senegalese nationality and being interviewed by a health-care worker with the same native language as the immigrant were significantly associated with completion of screening for LTBI. In the multiple logistic regression, being interviewed in the native language of the health-care worker (OR 2.5, 95% CI 1.3-4.8, P = 0.004) and being of Senegalese origin (OR 2.3, 95% CI 1.4-3.6, P = 0.0005) were independently associated with adherence to LTBI screening. Our results suggest that knowledge of the sociodemographic characteristics of immigrants, and the participation of health-care workers of the same cultural origin as the immigrant during the visits, can be an important tool to improve completion of screening for LTBI.

Differential Diagnosis of Cervical Mycobacterial Lymphadenitis in Children

Background and Aims: The differential diagnosis between tuberculosis (TB) and lymphadenitis caused by nontuberculous mycobacteria (NTM) in children is often based on epidemiologic and clinical data. The aim of this study was to identify epidemiologic and clinical variables associated with TB lymphadenitis in children attending 2 TB out-patient clinics in northern Italy during a 10-year period. Patients and Methods: All children less than 16 years of age attending the study sites suspected of mycobacterial disease from 1999 through 2008 were included in the analysis. Logistic regression was used to evaluate the variables independently associated with TB lymphadenitis. Results: From 299 children diagnosed with mycobacterial disease 121 children (40%) had a clinical diagnosis of cervical mycobacterial lymphadenitis: 38 TB (31%) and 83 NTM lymphadenitis (69%) cases. Increasing age (OR, 1.29; 95% CI, 1.02–1.69; P = 0.04), being foreign born (OR, 11.60; 95% CI, 1.37–114.20; P = 0.02), and having an abnormal chest radiograph (OR, 18.32; 95% CI, 2.37–201.68; P = 0.008) were independently associated with TB lymphadenitis. In the selected model, a 5-year-old foreign born child with cervical lymphadenitis and abnormal findings on chest radiograph has an estimated 0.90 probability of having TB disease. On the other hand, an Italy born child of the same age with cervical lymphadenitis and normal chest radiograph has a 0.04 probability of having TB. Conclusion: Epidemiologic and clinical data are useful tools in the differential diagnosis between TB and NTM lymphadenitis when etiologic diagnosis is not available.

Vaginal colonization with Candida spp. in human immunodeficiency virus – infected women: a cohort study

We have conducted a longitudinal study on factors associated with candidal vaginal colonization, a precursor of vaginitis, in a cohort of HIV-infected women in Italy. All consecutive women attending a single, tertiary care clinical site were offered free screening for sexually transmitted infections and genital disorders every 6–12 months. Candidal vaginal colonization was defined as a positive culture for Candida spp. in an asymptomatic woman. From January 1998 to July 2002 we analysed 214 women. The baseline prevalence of candidal vaginal colonization was 16.8%. In the logistic regression analysis, the time since HIV infection ≥36 months (odds ratio [OR] = 0.18, 95% confidence interval [CI] 0.016–0.53, P = 0.002) and a plasma viral load ≥10,000 copies/mL (OR = 3.9, 95% CI 1.03–14.9, P = 0.045) were independently associated with candidal colonization. Among 130 women who were followed for a mean period of 24 months, the incidence of vaginal colonization was 10.7/100 women-years. In the Cox regression analysis, a CD4+ T-lymphocytes count <100 cells/μL during the follow-up was associated with an increased risk of candidal vaginal colonization (OR = 4.45, C.I. = 1.20–16.81, P = 0.03). Risk of candidal vaginal colonization episodes in HIV-infected women significantly increase when CD4+ T-lymphocytes are less than 100.