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Contents:

Research
TB and HIV
Infection
Population Studies
Drug Reactions
June 2016
Molecular studies
Children
Treatment
Extra-Pulmonary TB
Risk Factors
Laboratory Studies

Research

The association between exaggeration in
health related science news and
academic press releases: retrospective
observational study.
M. tuberculosis EM Photo
Sumner et al Cardiff, Swansea, UK;
Sydney, Wollongong, NSW, Australia.
Forthcoming Meetings
BMJ 2014;349: g7015
Objective: To identify the source (press releases or
news) of distortions, exaggerations or changes to
the main conclusions drawn from research that
could potentially influence a reader's health-related
behavior.
Design: Retrospective quantitative content
analysis.
Setting: Journal articles, press releases and related
news with accompanying simulations.
Sample: Press releases ( n=462) on biomedical and
health related science issued by 20 leading UK universities in 2011, alongside their associated peer reviewed research papers and news stories (n=668).
Main outcome measures: Advice to readers to
change behavior, causal statements drawn from Dr John Thompson Canberra
correlational research, and inferences to humans from animal research that went beyond those in E/Prof Adrian Sleigh, Australian National
associated peer reviewed papers University, Canberra
Results: 40% (95% CI 33%-46%) of the press
releases contained exaggerated advice, 33% (26%- Address for correspondence 40%) contained exaggerated causal claims, and 36% (28%-46%) contained exaggerated inference to humans from animal research. When press releases contained such exaggeration, 58% ( 48%- Web page: tbreviewdotcom 68%), 81% ( 70%-93%)and 86% ( 77%-95%)of news stories respectively, contained similar exaggeration, compared with exaggeration rates of 17% (10%-24%), 18% (9%-27%) and 10% (0-19%) in news where the press releases were not exaggerated. Odds ratios for each categories of analysis were 6.5% (95% CI 3.5 to 12), 20 (7.6 to 51) and 56 (15 to 211). At the same time there was regimen with at least 3 active anti-tuberculosis little evidence that exaggeration in press releases drugs, Those who started fewer than 3 anti increased the uptake of news. tuberculosis drugs, were at a higher risk of Conclusions: Exaggeration in news is strongly
tuberculosis related death (aHR 3.17; 95% CI associated with exaggeration in press releases. 1.83-5.49)( as were those who did not have Improving of academic press releases could baseline drug susceptibility tests (2.24; 1.31-3.83). represent a key opportunity for reducing misleading Other prognostic factors for tuberculosis-related health related news. mortality were disseminated tuberculosis and a low Comment: This study confirms what we have long
CD4 cell count. 18% of patients were receiving ART at time of diagnosis in Eastern Europe compared with 44 % in Western Europe and 39% in Latin Europe (p< 0.0001) 12 months later the proportions were 67 % in Eastern Europe, 92% in TB and HIV
Western Europe and 85% in Latin America ( p< 0.0001) Interpretation: Patients with HIV and tuberculosis
Tuberculosis-related mortality in people
in Eastern Europe have a risk of death nearly 4 living with HIV in Europe and Latin
times than that in patients from Western Europe America: an international cohort study.
and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack if drug-susceptibility testing and suboptimal initial Podlekareva et al HIV Study Group
anti tuberculosis drug treatment in settings with a Eurocord
high proportion of drug resistance. Urgent action is needed to improve tuberculosis care for patients The Lancet HIV 2016; March e 120
living with HIV in Eastern Europe. Comment: The fall of Communism may have
brought many benefits to the citizens of eastern
Background: Tuberculosis in patients with HIV in
European countries, but not in the control of Eastern Europe is complicated by the high contagious diseases such as TB and HIV, especially prevalence of drug-resistant tuberculosis, low rates in their prison systems. of drug-susceptibility testing and poor access to antiretroviral therapy (ART), We report 1 year mortality estimates from a multi-region Eastern Europe, Western Europe and Latin American Isoniazid exposure and pyridoxine levels
prospective cohort study: the TB: HIV Study. in human immunodeficiency virus
Methods: Consecutive HIV-positive patients aged
associated with distal sensory
16 years or older with a diagnosis of tuberculosis neuropathy.
were enrolled from 62 tuberculosis and HIV clinics in 19 countries in Eastern Europe, Western Europe and Latin America, The primary endpoint was Van de Watt Cape Town, South Africa;
death within 12 months after stating anti- Miami, Fl, Atlanta. Ga, USA
tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis Int J Tuberc Lung Dis 2015; 19:1312
related. Follow-up was until death, the visit or 12 months after baseline, whichever occurred first. Setting: Distal sensory polyneuropathy (DSP)
Risk factors for all-cause and tuberculosis –related may manifest in human immunodeficiency virus deaths were assessed using Kaplan-Meier estimates (HIV) infected individuals before or after antiretroviral therapy (ART). DSP can also occur Findings: Of 1406 patients (834 in Eastern Europe,
in response to isoniazid (INH): this can be 317 in Western Europe and 255 in Latin America, prevented by pyridoxine supplementation. N- 264 (19%) died within 12 months. 188 (71%) of acetyltransferase 2 (NAT2) polymorphisms these deaths were tuberculosis related. The influence drug acetylation and possibly the risk for probability of all cause death was 21%(95% CI 26- INH-associated DSP. 32) in Eastern Europe, 4% in Western Europe Objective: To investigate the relationship between
(95% CI 3-7)and 11% in Latin America (95% CI 8- previous/current TB, pyridoxine deficiency and 16) (p<0.0001) and the corresponding probabilities DSP in HIV-infected individuals enrolled in a of tuberculosis deaths were 23% (20-26), 1% (0-3), government sponsored HIV programmed. and 4% (2-8), respectively (p<0.0001). Patients Design: Neuropathy assessments were performed
receiving care outside Eastern Europe had a 77% among 159 adults pre-ART and 12 and 24 weeks decreased risk of death; adjusted HR 0.23(95% CI thereafter. DSP was defined as >1 neuropathic 0.16-0.31) compared with patients who started a symptoms and sign. NAT2 genotypes predicted Conclusions: The care of TB/HIV co-infected
acetylation phenotype. Serum pyridoxine levels patients have shown sustained improvement in (PLP) were quantified at baseline and week 12. Vietnam. Rising numbers of MDR-TB cases is a Results: DSP was present in 16% of individuals
concern, but this this not driven by HIV co- pre-ART and was associated with previous/current TB (p = 0.020). Over 50% were pyridoxine Comment: We are not told how many TB isolates
deficient (PLP <25 nmol/L, despite are of the Beijing stain and more likely to cause supplementation with vitamin B complex (2-4 mgs/day pyridoxine). Those with a history of TB and pre-ART were more likely to be pyridoxine deficient (p = 0.029) , and slow/intermediate Infection:
phenotypes impacted on their PLP levels. Incident/worsening DSP after ART developed in 21 % of the participants. PLP levels remained low Risk of active tuberculosis in the 5 years
after ART, particularly in those with prior TB, but following infection….15%?
without an association between DSP and NAT2 Trauer et al Melbourne, Vic;
Conclusion: Adequate pyridoxine
supplementation before ART initiation should be
Townsville, Qld, Australia.
prioritized, particularly in those with a history of TB or current TB. Chest 2016; 149: 516
Comment: A study done in Madras (Chennai) in
1963 suggested that the daily dose of pyridoxine Background: It is often stated that the lifetime risk
should not be less than 6 mg, nor exceed 25mg. of developing active TB after an index infection is 5% to 10%, one half of which accrues in the 2 to 5 years following infection. Tuberculosis and HIV co-infection in
Methods: This study included close contacts of
Vietnam.
individuals with active pulmonary tuberculosis notified in the Australian state of Victoria from Trinh et al Sydney, NSW, Australia;
January 1 2005 to December 31, 2013, who we deemed to have been infected as a result of their Hanoi, Vietnam; Paris, France.
exposure. Survival analysis was first performed on the assumption of complete follow-up through to Int J Infect Dis 2016; 46: 58
the end of the study period. The analysis was then repeated with imputation of censorship for Introduction: Tuberculosis (TB) and human
migration, death and preventive treatment, using immunodeficiency virus (HIV) infection are local mortality and migration data combined with leading causes of disease and death in Vietnam, but programmatic data on the administration of TB/HIV disease trends and the profile of co- preventive therapy. infected patients are poorly described. Results: Of 613 infected close contacts, 67(10.9%)
Methods: We examined national TB and HIV
developed active TB during the study period. notification data to provide a geographic overview Assuming complete follow-up, the 1,650-day and describe relevant disease trends within cumulative hazard was 11.5% (95% CI, 8.9-14.1). Vietnam. We also compared the demographic and with imputation of censorship for death, migration clinical profiles of TB patients with and without and preventive therapy, the median 1,650 cumulative hazard over 10,000 simulations was Results: During the past 10 years (2005-3015)
14.5 (95 % CI, 11.1-17.2). Most risk accrued in the cumulative HIV case numbers and deaths increased first 5 months after infection and risk was greatest to 298,151 and 71,332 respectively, but access to in the group aged less than 5 years, reaching 56% antiretroviral therapy (ART) improved and new with imputation, but it was also elevated in older infections and deaths declined. From 2011-2014 children (27.6% in the group 5-15%) routine HIV testing increased from 58.1% to 72.5% Conclusions: The risk of active TB following
and of all TB patients diagnosed with HIV in 2014, infection is several –fold than traditionally accepted 2,803 (72.4%) received ART. The number of estimates, and is particularly high immediately multidrug resistant (MDR)-TB cases enrolled for following infection and in children. treatment increased almost 3-fold (578 to 1532) Comment: A figure of 50% for infants has been
from 2011 to 2014. The rate of HIV co-infection in noted before, but not as much as 27.6% for older MDR and non-MDR TB cases 51/1532; 3.3% vs children. Presumably the vast majority of index 3774/100,555; 3.8%; OR 0.77, 95% CI 0.7-1.2) cases would have been come from countries where was similar in 2014. TB and HIV were prevalent., although the numbers of HIV positive cases introduced to Australia are Population Studies
sill small. However, the tuberculin used in the original studies was very different from that now available, so the accurate diagnosis of infection Mortality among tuberculosis cases in
might be suspect. Finally, an Australia-wide study Victoria, 2002-2013: case fatality and
of this kind, where more subjects can be recruited, factors associated with death.
Dale et al Melbourne, Vic., Australia
Initiation and completion rates for
latent tuberculosis infection treatment:
Int J Tuberc Lung Dis 2016; 20: 515
a systematic review.
Setting: The state of Victoria, Australia, is an
industrialized setting with low tuberculosis (TB)
incidence, universal health care and high levels of Sandgren et al Stockholm, Sweden;
Rotterdam, the Netherlands.
Objective: To assess case fatality rates (CFRs) and
factors associated with death in a cohort of TB BMC Infect Dis 2016; 16: 204
cases notified between 2002 and 2013.
Design: Retrospective cohort study. Cases who
died untreated or during treatment were reviewed Background: Control of latent tuberculosis
to determine whether TB was a primary cause of, infection (LTBI) is an important step towards contributed to, or was unrelated to death. tuberculosis admission. Preventive treatment will Descriptive and multivariate analyses were used to prevent the the development of disease in most compare demographic, clinical and pathological cases of diagnosed with LTBI. However, low characteristics. initiation and completion rates affect the Results: Of 3056 cases, 198 (5.0%) died of any
effectiveness of preventive treatment. The cause. TB was the primary cause of death in 99 objective was to systematically review data on cases (50.3%) and contributed to death in a further initiation rates and completion rates for LTBI 34 cases, giving a TB-related (CFR) of 3.4%. In treatment regimens in the general population and multivariate analysis, TB-related mortality reduced specific populations with LTBI. over time, and was positively associated with male Methods: A systematic review of the literature sex, older age, history of substance abuse and (PubMed, Embase) published up to February 2014 disseminated or meningeal TB. Factors associated with survival included having a history of past Results: Forty-five studies on initiation rates and
travel to or residence in a high TB risk country, 83 studies on completion rates of LTB treatment lymph node TB or extrapulmonary TB were found. These studies provided initiation rates manifestations, excluding meningeal, (IR) and completion rates (CT) in people with genitourinary, pleural and lymph node TB. LTBI among the general population (IR 26-99%, Conclusions: TB CFRs in this setting are among
CR 39-96%),case contacts (IR 34-40-95%,48- the lowest reported globally. TB mortality steadily 82%), healthcare worker (IR47-98%CR 17-79%), decreased from 2002 to 2013. the homeless (IR 34-90%, CR 23-71%, people who Comment: I assume the reference to lymph node
inject drugs(IR 52-91%, CR 38-89%), HIV- TB on two occasions referred to intrathoracic and infected individuals (IR 67-92%, CR 55-95%), extrathoracic node TB. There was a time when inmates (IR 7-90%, CR 4-100 %), Immigrants (IR having your scrofula touched by a monarch was 23-97%, CR 7-86%) and patients with associated with survival. comorbidities (IR 82-93, CR75-92%). Generally, completion rates were higher for short than for long LTBI treatment regimens.
Conclusion: Initiation and completion rates for
Causes of death in Vanuatu
LTBI treatment regimens were frequently suboptimal and varied greatly within and across Carter et al Noumea, New Caledonia;
different populations. Port Vila, Vanuatu; Canberra,
Comment: No great surprises here, but how some
Brisbane, Melbourne, Sydney, Australia
studies reached 90+% CR, (one, even 100%) needs further analysis . Popul Health Metr 2016; 14:7

Background: The population of the Pacific
Melanesian country of Vanuatu was 234,000 at the
2009 census. Apart from subsistence activities, Aia et al Port Moresby, New Guinea;
economic activity includes tourism and agriculture. Brisbane, Qld, Australia; London, UK;
Current completeness of vital registration is Geneva, Switzerland; Manila,
considered too low to be useable for national statistics; mortality and life expectancy (LE) are derived from indirect demographic estimates from censuses/surveys. Some cause of death (CoD) data PLoS One 2016; 11: e0149806
are available to provide information on major causes of premature death. Background: Reliable estimates of the burden of
Methods: Deaths 2001-2007 were coded for cause
multidrug-resistant tuberculosis (MDR-TB) are (ICDv10) for ages 0-59 years from hospital crucial for effective control and prevention of separations (HS) (n=636), hospital medical tuberculosis (TB). Papua New Guinea is a high TB certificates (MC) of death and monthly reports burden country with limited information on the from community health facilities (CHF) (n=1,169). magnitude of the MDR-TB problem. Ill-defined causes were 3% for hospital deaths and Methods: A cross-sectional study was conducted
20% from CHF. Proportional mortality was in four PNG provinces: Madang, Morobe, National calculated by cause (excluding ill-defined) and age Capital District and Western Province. Patient 0-4,5-14 years and also by sex for 15-59 years. sputum samples were tested for rifampicin From total deaths by broad age group and sex from resistance by the Xpert MTB/RIF and those 1999 and 2009 census analyses, community deaths showing the presence of resistance underwent were estimated.by a weighted average of MC and phenotypic susceptibility to first and second –line anti-TB drugs including streptomycin, isoniazid, Results: National estimates indicate main causes of
rifampicin, ethambutol, pyrazinamide, ofloxacin, death <5 years perinatal disorders (45%) and amikacin, kanamycin and capreomycin. malaria, diarrhea and pneumonia (27%). For 15-59 Results: Among 1182 TB patients enrolled in the
years, main causes of male deaths were circulatory study, MDR-TB was detected in 20 new cases disease 27%, neoplasms 13%, injury 13%, liver (2.7%:95%CI 1.1-4.3) and 24 previously treated disease 19%, infection 18%, diabetes 7% and (19.1; 95% CI 8.5-29.5%) TB cases. No case of chronic respiratory disease 7%; and for females: extremely drug-resistant TB (XDR-TB was neoplasms 29%, circulatory disease 15%, detected. Thirty percent (6/20) of new and 33.3% diabetes10%, infection 9% and maternal deaths (8/24) of previously treated with MDR-TB were 8%. Infection included tuberculosis, malaria and
detected in a single cluster in Western Province. viral hepatitis. Liver disease (including hepatitis Conclusion: In PNG the proportion of MDR-TB in
and cancer) accounted for 18% of deaths in adult new cases is slightly lower than the regional males and 9% in females. Non-communicable average of 4.4% (95%CI 2.6-6.3%). A large disease (NCD) including circulatory disease and proportion of MDR-TB cases were identified from chronic respiratory disease accounted for 52% of a single hospital in Western Province, suggesting premature deaths in adult males and 60 % in adult that the prevalence of MDR-TB across the country females. Injuries accounted for 13 % in adult is heterogeneous. Future surveys surveys should males 6% in adult females. Maternal deaths further explore this finding. The survey also helped strengthen the use of smear microscopy and an annual maternal mortality ratio of 130/100.000 Xpert MTB/RIF testing as diagnostic tools for TB Conclusion: Vanuatu manifests a double burden of
Comment: From the experience of Papuans in the
disease with significant proportional mortality from Western Province who flocked to the Torres Straits perinatal disorders and infection/pneumonia <5 to have their drug –sensitive TB treated, this region years and maternal mortality, coupled with of PNG had a TB control program which was one significant proportional mortality in adults (15-59 of the worst in the country. Let's hope the years) from cardiovascular disease (CVD), injection of Australian money and resources into neoplasms and diabetes. Daru and the Western Province for TB control will Comment: It would appear that tuberculosis is
seriously underreported.
The burden of drug-resistant
tuberculosis in Papua New Guinea:
results of a large population – based
survey.

Drug Reactions
circumstances it seems illogical to continue serial liver function tests, particularly as we know that most who develop abnormal LFTs during treatment Baseline abnormal liver function tests
will see them return to normal even if the drug is are more important than age in the
development of isoniazid-induced
hepatoxicity for patients receiving
Molecular Studies
preventive therapy for latent
tuberculosis infection.
Mycobacterium tuberculosis whole
genome sequencing and protein
Gray et al Sydney, NSW, Australia
structure modelling provides insights
into anti-tuberculosis drug resistance.
Int Med J 2016; 46: 281
Phelan et al Sydney, NSW, Australia;
Background: One of the cornerstones of
London, Cambridge, UK; Cape Town,
Australia's public health programs to eliminate South Africa; Belo Horizonte, Brazil;
tuberculosis (TB) is the identification and treatment Antwerp, Belgium; Thuwal, Saudi
of latent tuberculosis infection (LTBI)
Aims: the aim of this study is to determine
Arabia; Geneva, Switzerland
demographics, compliance, completion rates and BMC Med 2016; 14: 31
adverse events of patients on preventive therapy (PT) for LTBI at our institution. The secondary Background: Combating the spread of drug
aim is to determine he rates of isoniazid resistant tuberculosis is a global health priority. hepatoxicity and identify any contributory factors. Whole genome association are being applied to Methods: The method used was an audit using
identify genetic determinants of resistance to anti- medical records of 120 consecutive patients. (2010- tuberculosis drugs. Protein structure and 2014) treated with PT for LTBI. interaction modelling are used to understand the Results: Seventy two patients with confirmed with
functional effects of putative mutative mutations LTBI started 9 months of INH and 22 started 4 and provide insight into the molecular mechanisms months on rifampicin (RIF). The median age was leading to resistance. 30 years. Half the patients were born in high TB Methods: To investigate the potential utility of
prevalence countries. Fifty six percent were these approaches, we analysed the genomes of 144 contacts of index cases with confirmed TB, and Mycobacterium tuberculosis clinical isolates from 26% were pre-immunosuppression. Seventy seven the Special Programme for Research and Training percent completed therapy with adequate in Tropical Diseases (TDR) collection sourced compliance. Thirty three per cent on isoniazid and from 20 countries in four continents. A genome- twenty three percent on RIF experienced some liver wide approach was applied to 127 isolates was function test abnormality while on treatment. INH applied to to identify polymorphisms associated was ceased in 3 % due to asymptomatic hepatitis with MICs for first –line anti-tuberculosis drugs. (transaminases > 5times upper limit of normal). In addition, the effect of identified candidate No patients had permanent liver damage. mutations on protein stability and interactions were Significant risk factors for liver dysfunction were assessed quantitatively with established risks for liver disease (p=0.03) or abnormal pre- computational methods. therapy LFT (P<0.001), No patients developed Results: The analysis revealed thar mutations in
the genes rpoB (rifampicin), katG (isoniazid), Conclusion: The completion rate of 77% and rate
inhA-promotor (isoniazid) rpsL (streptomycin) and of INH induced hepatic dysfunction of 3% is embB (ethambutol) were responsible for the compatible with the literature. We found no age majority of resistance observed. A subset of the association with the risk of INH-induced hepatic mutations identified in rpoB and katG were dysfunction, however, there was a significant and predicted to affect protein stability. Further, a linear association with the degree of liver strong correlation was observed between the MIC dysfunction during INH therapy and the presence values and the distance of the mutated residues in of abnormal baseline LFT. Routine LFT the three-dimensional structures of rpoB and katG monitoring allowed early cessation of INH in those to their respective drugs binding sites. with significant but asymptomatic hepatitis who did Conclusions: Using the TDR resource, we
not meet criteria for ATS/ CDC LFT monitoring. demonstrate the usefulness of whole genome Comment: If base line LFTs are abnormal should
association and convergent evolution approaches to we be treating with INH anyway? In those detect known and potentially novel mutations associated with drug resistance. Further, protein satisfactory; 89.4% of children had completed structural modelling could provide a means of treatment or were cured. predicting the impact of polymorphisms on drug Conclusions: The burden of paediatric TB in
efficacy in the absence of phenotypic data. These Australia is low, but has not changed over the past approaches could ultimately lead to novel decade. The highest rates are among children born resistance mutations to improve the design of overseas, emphasizing the important role of tuberculosis control measures, such as diagnostics, immigration screening as Australia aspires to and inform patient management. Comment: Provided the cost of new diagnostics
Comment: At least this should involve clinical
falls within the budget of those countries that need assessment and concurrent blood and intradermal Children
Dilemma of managing asymptomatic
children referred with "culture-
confirmed" drug-resistant tuberculosis.
The epidemiology of tuberculosis in
children in Australia, 2003-2012
Loveday et al Tygerberg, Durban,
South Africa; Sydney, NSW, Australia;
Teo et al Sydney, NSW, Melbourne,
Bronx, NY, USA
Vic. , Darwin, NT, Australia.
Arch Dis Child 2016; April: pii
Med J Aust 2015; 203: 440
Background: The diagnosis of drug-resistant
tuberculosis (DR-TB) in children is challenging
Objective: To describe the burden and trends in
and treatment is associated with many adverse paediatric tuberculosis (TB) in Australia between Objective: We aimed to assess if careful
Design: A retrospective analysis of TB data from
observation, without initiation of second-line the the National Notifiable Diseases Surveillance treatment is safe in asymptomatic children referred System (NNDSS) on TB in children (under 15 with "culture –confirmed ".DR-TB years of age) during the 10-year period, 2003-2012. Setting: KwaZulu-Natal, South Africa, an area
Results: TB notifications in Australia during the
with high burdens of HIV, TB and DR-TB. study period included 538 children (range, 37-66 cases per year), representing a 4.6% of the total Design, Intervention and Main Outcome
Measures: We performed an outcome review of
case load during the period (range 3.8%-5.8% each children with "culture-confirmed" DR-TB who year). Place of birth was recorded for 524 (97.4%); were not initiated on second-line TB treatment, as of these 230 (43.9%) were born in Australia, 294 they were asymptomatic with normal chest (56.1%) overseas. The average annual notification radiographs on examination at our specialist rate was 1.31 (95% CI 1.20-1.43) cases per 100,000 referral hospital. Children were followed up every child population. The rate was highest for other month for the first year, with a final outcome overseas-born than for Australian-born children, assessment at the end of the study. (9.57 [95% CI 8.51-10.73] v 0.61[95% CI 0.53- Results: In total, 43 asymptomatic children with
0.69]) cases per 100,000 children. The overall rate normal chest radiographs were reviewed. The was highest among those aged 0-4 years. The median length of follow-up until final evaluation annual notification was three times higher for was 549 days (IQR 259-722days); most (34; 83%) Indigenous children than for nonindigenous children were HIV uninfected. Resistance patterns Australia born children. Of 427 patients (79.4% of included 9 (21%) monoresistant and 34 (79%) total) for whom the method of case detection was multidrug-resistant (MDR) strains. Fifteen children recorded, 37.0% were detected by contact (35%) had been treated with first-line TB screening, 8.78% by post-arrival immigration treatment, prior to presentation to our referral screening and 54.3% by passive case detection. hospital. At the final evaluation, 34 (80%) children Pulmonary tuberculosis was the most common were well. 7(16% ) were lost to follow- up. 1 (2%) diagnostic classification (64.7% of patients). The received MDR-TB treatment and 1 (2%) died of most common risk factors were close contact with a unknown causes. The child who received MDR- TB case and recent residence in a country with a TB treatment developed new symptoms at the 12 – high incidence of TB, Treatment outcomes were month review and responded well to second line-treatment. Conclusions: Bacteriological evaluation should
Comment: If inhalable rifampicin was used, it
not be performed in the absence of any clinical would obviate the need to ingest it on an empty indication. If drug-resistance Mycobacterium tuberculosis is detected in an asymptomatic child with a normal chest radiograph, close observation may be appropriate strategy, especially in settings A pharmacokinetic evaluation of
where potential laboratory error and poor record keeping are constant challenges. sulfamethoxazole 800 mgs once daily in
Comment: Before nuclear studies were available,
the the treatment of tuberculosis.
false positive cultures were not rare, but a trip to the laboratory concerned usually resolved the Alsaad et al Groningen, Nijmegen,
problem without subjecting the patient to prolonged Bilthoven, The Netherlands.
Antimicrob Agents Chemother 2016;
Treatment:
Dry powder inhalable formulations for
Abstract: For treatment of multidrug-resistant
anti-tubercular therapy.
tuberculosis (MDR-TB) there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates and already Parumasivum et al Sydney, NSW,
frequently co-prescribed in TB-HIV co-infected Australia; Amman, Jordan
patients. However, only limited data are available on pharmacokinetic (PK) and pharmacokinetic Adv Drug Deliv Rev 2016; May 17: pii
(PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate PK parameters and in vitro PD data of the effective part of co-trimoxazole; sulfamethoxazole. In a Abstract: Tuberculosis (TB) is an intracellular
prospective PK study in patients with drug- infectious disease caused by the airborne susceptible TB (age>18), SXTwas administered in bacterium, Mycobacterium tuberculosis. Despite a dose of 960 mg daily. One-compartment considerable research efforts, the treatment of TB continues to be a great challenge in part due to the Pharmacokinetic modelling was performed using requirement of prolonged therapy with multiple Mw (pound) harm3.81 (Mediware Groningen, the high-dose drugs and associated side effects. The Netherlands). The fAUC/MIC ratio and the and the delivery of pharmacological agents directly to the timeperiod in which the free concentration respiratory system, following the natural route of exceeded the MIC (T>MIC) were calculated. infection, represents a logical therapeutic approach Twelve patients received 960 mgs co-trimoxazole for treatment or vaccination against TB. on top of first line drugs. The pharmacokinetic Pulmonary delivery is non-invasive, avoids first– parameters of the population model were as follows pass metabolism in the liver and enables targeting (geometric mean+/- SD: metabolic clearance of therapeutic agents to the infection site. Inhaled (CLm) 1.57+/- L/h, volume of distribution (Vd) delivery also potentially reduces the dose 0.03+/_0.13, gamma distribution rate constant requirement and the accompanying side-effects. (Ktr_po 2.18+/- 1.143, gamma distribution shape Dry powder is a stable formulation of drug that can factor (n po) 2.15 +/- 0.39. Free fraction of be stored without refrigeration compared to liquids sulfamethoxazole was 0.3, but ranged between 0.2- and suspensions. The dry powder inhalers are easy 0.4. The median value of the MICs was 9.5 mg/L to use and suitable for high-dose formulations. (IQR 4.75-9.5) and of f AUC/MIC was 14.3(IQR This review focuses on the current innovations of 13.0-17.5). The percentage of f T> MIC ranged inhalable dry powder formulations of drug and between 43 and 100% of the dosing interval, The vaccine delivery for TB, including the powder PK and PD data from this study are useful to production method, preclinical and clinical explore a future dosing regimen of cotrimoxazole evaluations of inhaled dry powder over the last for MDR-TB treatment. decade. Finally the risks associated with Comment: There seems to be some confusion over
pulmonary therapy are addressed. A novel dry what dose of sulfamethoxazole the patients were powder formulation with high percentages of given. The standard dose is 800 mg daily. respirable particles coupled with a cost effective inhaler device is an appealing platform for a TB WHO recommends rapid test, shorter
Comment: Presumably one would administer the
drug regimen for MDR-TB
Xpert RIF test first. JT Brooks M Geneva
Comparison of effectiveness and safety
of imipenin/clavulanate versus
Medscape.com 2016; 19 May
meropenem/clavulanate containing
regimens in the treatment of MDR-and
The World Health Organisation (WHO) today issued new recommendations designed to speed up detection and improve treatment of multidrug- resistant tuberculosis (MDR-TB), The Tiberi et al Sassari, Rome, Brescia,
recommendations call for use of a novel rapid Varese, Italy; London, UK;Lugano,
diagnostic to rule out resistance to second-line Switzerland; Sao Paulo, Brazil; Paris,
drugs and a shorter cheaper regimen for MDR-TB. France; Lima, Peru; Groningen, Hague,
The new treatment regimen can be completed in 9 to 12 months, rather than the typical 18 to 24 The Netherlands; Las Palmas, Spain;
months, and is less expensive than current Athens, Greece; Minsk, Belarus; Ruzo-
mberok,Slovakia; Guayaquil, Ecuador;
The shorter regimen is recommended for patients Brussels, Belgium.
with uncomplicated MDR-TB; for example, those individuals whose MDR-TB is not resistant to the more important second-line drugs used to treat Eur Respir J 2016; Apr 13
MDR-TB (fluoroquinolones and injectables). The shorter regimen is also recommended for people Abstract: No large study to date has ever evaluated
who have not yet been treated with second-line the effectiveness, safety and tolerability of imipenim/clavulanate versus meropenem/ The shorter regimen includes an intensive treatment clavulanate to treat multidrug –and extensively phase, lasting 4 to 6 months and consisting of four drug-resistant tuberculosis (MDR-TB and XDR- second –line drugs, and a continuation phase TB. The aim of this observational study was to lasting 5 months and composed of two drugs. The compare the therapeutic contribution of seven recommended drugs are kanamycin, imipenin/clavanulute versus meropenem/ moxifloxacin, prothionamide, clofazamine, clavanulate added to back-ground regimens to pyrazinamide, high dose isoniazid and ethambutol. treat MDR-and XDR-TB. cases. 84 patients treated The recommendations on the shorter regimens are with imipenem/clavulanate containing regimens based of initial studies involving 1200 patients with showed a similar median number of antibiotic uncomplicated MDR-TB in 10 countries, and are resistances (8 versus 8) but more fluoroquinolone expected to benefit the majority with MDR-TB resistance (79% versus 48.9%, p, 0.0001) and worldwide. However, there are serious risks for higher XDR-TB prevalence (67.9% versus 49.0 %, worsening resistance if the shorter regimen is used P=0.01) in comparison with 96 patients exposed to inappropriately (ie in patients with extensively meropenem/clavulanate containing regimens. drug-resistant (XDR-TB). Patients were treated with imipenem/clavulanate The WHO also recommends national TB reference and meropenem/clavulanate= containing regimens laboratories now use a novel rapid diagnostic to for a median (interquartile range ( of 187 (60-428) rule out resistance to to second-line drugs. The versus 85 (49-156) days, respectively. Statistically DNA-based test called MTBDRs1 identifies significantly differences were observed on sputum genetic mutations in MDR-TB strains, rendering smear and culture conversion rates (79.7% versus them resistant to fluoroquinolones and injectable 94.8%, p= 0.03) and 71.9% versus 94.8 % p< second-line drugs. This test yields results in just 0.0001, respectively) and on success rates (59.7% 24-48 hours down from the 3 months or longer as versus77.5%, p=0.03. Adverse events to currently required. The much faster turnaround imipenem/clavulanate and meropenem/clavulanate time means that MDR-TB patients with additional were reported in 5.4% and 6.5% of cases only. Our resistance are not only diagnosed more quickly, but study suggests that meropenem/clavulanate is more can be placed on appropriate second-line regimens. effective than imipenem/clavulanate in treating The MTBDRsI test is also a critical prerequisite for M/XDR –TB patients. identifying patients with MDR-TB eligible for the Comment : It would be reassuring to compare the
new shorter treatment regimen, while avoiding results from individual centers. putting patients who have resistance to second- line drugs on the shorter regimen which could contribute to the development of XDR-TB. Propensity score-based approaches to
Extrapulmonary tuberculosis
confounding by indication in individual
patients data meta-analysis: non-
High rate of drug resistance among
standardised treatment for multidrug
tuberculous meningitis cases in Shaanxi
resistant tuberculosis.
province, China.
Fox et al Sydney, NSW, Australia;
Wang et al Xi'an, Shaanxi, Kunming,
Montreal, Canada.
Yunnan, Beijing, PR China; Sydney,
NSW, Australia.
PLOS one 2016; March 29
Sci Rep 2016; 6: 25251
Background: In the absence of randomized
clinical trials, meta-analysis of individual patient Abstract: The clinical and mycobacterial features
data (IPD) from observational studies may provide of tuberculous meningitis (TBM) cases in China the most accurate effect estimates for an are not well described, especially in western intervention. However, confounding by indication provinces with poor tuberculosis control. We remains an important concern that can be addressed prospectively enrolled patients in whom TBM was by incorporating individual patient covariates in considered in Shaanxi province, northwestern different ways. We compared different analytic China, over a two-year period (September 2010 to approaches to account for confounding in IPD from December 2012). Cerebrospinal fluid specimens patients for multidrug-resistant tuberculosis. were cultured for Mycobacterium tuberculosis, Methods: Two antibiotic classes were evaluated;
with phenotypic and genotypic drug susceptibility fluoroquinolones-considered the cornerstone of testing (DST), as well as genotyping of all positive effective MDR-TB treatment.- and macrolides, cultures. Among 350 patients included in the which are known to be safe, yet are ineffective in study, 27(7.7%) had culture confirmed TBM; 84 vitro. The primary outcome was treatment success (24.0%) had probable and 239 (68.4%) had against treatment failure failure, relapse or death. possible TBM. DST was performed on 25/27 Effect estimates were obtained using multivariate (92.3%) culture positive ; 12/25 (48.0%) had "any and propensity-score- based approaches. resistance" detected and 3 (12.0 %) were multidrug Results: Fluoroquinolone antibiotics were used in
resistant (MDR). Demographic and clinical 28 included studies, within which 6612 patients features of drug resistant and drug susceptible received a fluoroquinolone and 723 patients did TBM were similar. Beijing was the most common not. Macrolides were used in 15 included studies, (20/25; 80.0%) with 9/20 (45%)exhibiting drug within which 459 patients received this class of drug resistance; including all 3 MDR strains. All antibiotic 3670 did not. Both standard (4/4 ) isoniazid resistant strains had mutations in multivariable regression and propensity score– the katG gene. 75% (3/4) of strains with phenotypic based methods resulted in similar effect estimates rifampin resistance had mutations in the rpoB gene for early and late generation fluoroquinolone, while detected by Xprt MTB/RIF. High rates of drug macrolide antibiotics use was associated with resistance were found among culture- confirmed reduced treatment success. TBM cases; most were Beijing strains. Conclusions: In the individual patient data meta-
Comment: The absolute numbers of those resistant
analysis, standard multivariate and propensity – seem rather small. How many of the probable and score based methods of adjusting for individual possible responded to treatment. patient covariates for observational studies yielded produced similar estimates. Even when such adjustment is made for potential confounding, interpretation of adjusted estimates must still
consider the potential for residual bias.
Comment: We ae reminded that statistical analysis
has not yet reached perfection.
JT
Safety and efficacy of additional
Risk Factors
levofloxacin in tuberculous meningitis:
a randomized controlled pilot study.
Risk of tuberculosis after lung
transplantation: the value of
Kalita et al Lucknow, Uttar Pradesh,
pretransplant chest computed
tomography and the impact of m TOR
inhibitors and azathioprine use.
Tuberculosis (Edin) 2016; 98: 1
Guirao-Arrabal et al Cordoba, Spain
Background: Levofloxacin is an effective
bactericidal category 111 antitubercular drug. There is paucity of studies comparing the role of Transpl Infect Dis 2016; May 25
additional levofloxacin to standard antitubercular regimen in the patients with tuberculous meningitis Background: It is necessary to determine the
incidence and risk factors for tuberculosis (TB), as Aims: To compare the safety and efficacy of
well as strategies to assess and treat latent adding levofloxacin to standard four drug ATT tuberculosis infection (LTBI) in lung transplant Subjects and Methods: The patients with TBM
Methods: A retrospective cohort study of 398 lung
diagnosed on the basis of clinical, cerebrospinal transplant recipients was performed. Episodes of (CSF) and MRI criteria were included. Children TB were studied and the incidence rate was below 15 years, patients with pregnancy, seizures, calculated. Logistic regression analysis was used liver failure, kidney failure and malignancy were to analyzed specific variables as potential risk excluded. The baseline clinical, CSF and MRI characteristics were noted and consciousness was Results: Median follow-up was 558 days (1-6636).
evaluated by Glasgow Coma Scale (GCS). The Six cases (1.5%) of TB were documented in 398 patients were randomized to RHZE (rifampicin, transplant patients The incidence density was 406.3 isoniazid, pyrazinamide and ethambutol) RHZEL cases/100,000 patient years (95% CI 154.7-845), (RHZE and levofloxacin) groups. Outcome was which is higher than in the general population defined at 6 months. Primary outcome was death (13.1cases/100,000 person years). All cases and secondary outcomes were disability as assessed occurred in the period 1993-2006 when the by Barthel Index score and adverse events. tuberculin skin test (TST) and treatment of LTBI in Results: Out of 110 TBM patients screened, 57
positive TST were not part of the protocol. fulfilled the inclusion criteria. Their median age Pretransplant computed tomography(CT) showed was 35 (15-75) years. 29 patients received RHZEL residual lesions in 50% of patients who developed and 28 RHZE. The baseline clinical , biochemical TB, although the TST was negative and the chest and MRI characteristics were similar in both radiograph was inconclusive. Multivariate analysis groups. At 6 months, 11 (19.3%) patients died, 38 identified the presence of residual lesions in the (66.76%) had good and 7 (12.3%) poor outcome. pretransplant chest CT ( OR 11.5, 85%CI 1.9-69.1, There was insignificant survival benefit in RHZEL P=0.008), use of azathioprine (OR 10.6, 95% CI group compared to RHZE (HR- 2.61, 95%CI 0.73- 1.1-99, P= 0.038), and use of everolimus (OR 6.7, 9.36, P=0.14, 25% patients died in RHZE whereas 95% CI1.1-39.8, P=0.036) as independent risk 13.8% in RHZEL group. The disability was not significantly different between the two groups. The Conclusions: Residual lesions in the pretransplant
composite side effects were also similar between chest CTs and the use of azathioprine and nTOR the two groups except for a higher frequency of inhibitors are associated with the risk of TB. Comment: It is not clear that the authors have
In RHZEL group (5 vs 0) which resulted in made a case for routine CT chest scan of candidates withdrawal of levofloxacin. for organ transplant, particularly in countries with a Conclusion: There was insignificant survival
low TB incidence. benefit in RHZEL which was associated with high frequency of seizures. Comment: A disappointing result, although larger
number may have shown a difference. I am
pleased to see the authors using the long authorized
abbreviations for antituberculosis drugs, now
generally neglected.
JT

Laboratory Studies
Thermostability of IFN-Gamma and IP-
10 release assays for latent infection
with Mycobacterium tuberculosis: A
Tbnet study.
Blauenfeldt et al Copenhagen,Hillerod,
Roskild, Denmark; Freiburg, Borstel,
Lubeck, Germany; Windhoek, Namibia;
Stockholm, Sweden; Porto, Portugal; St
Gallen, Switzerland; Badalona, Spain.
Tuberculosis (Edin) 2016; 98: 7
Introduction: Interferon-gamma (INF-gamma
inducible protein 10kD (IP-10) and IFN-gamma release assays (IGRAs) are immunodiagnostic tests
aiming to identify the presense of specific cellilar
immune responses, interpreted as markers for latent
infection with Mycobacterium tuberculosis.
Incubation at higher temperatures could affectIFN-
gamma and IP-10 responsiveness in order to
Improve the performance of IP-10 release assays
ans IGRAs.
Aim; The aim of this study was to assess the
robstmess of whole blood based IP-10 release assay
and IGRAs and the effet of hyperthermic
incubation (39 C) on the diagnostic accuracyof IP-
10 release assay and IGRAs.
Results:We included 65 patients with confirmed
pulmonary tuberculosis and 160 healthy controls
from 8 European countries collaborating in the
Tbnet. In patients, IP=10 responses increased 1.07
(IQR 0.90-1.36) fold and IFN-gamma decreased
0.88 (IQR0.57-1.02( fold with 39 C compared to 37
C incubation temperature. At 37 C IGRA
sensitivity was 85% and IP-10 sensitivity was 82%,
whereas specificity was 97% for both tests (p>0.8).
These minor changes observed as a result of
hyperthermic incubation were not sufficient to
impact IGRA and IP-10 release assay test
performance.
Conclusion: The performance of IGRA and IP-10
release assays is robust despite variations in the
incubation temperature between 37 C and 39 C.
Comment: Are we to conclude that if these tests
ever became available in the primary health care
center , room temperature would not matter.
JT
Cavitating PTB- courtesy IUATLD

Source: http://www.thearc.org.au/_literature_154592/Australian_TB_Review_-_June_2016_Newsletter