H5N1

ECDC: Response plan to control and manage the threat of multi- and extensively drug-resistant gonorrhoea in Europe

ECDC has published Response plan to control and manage the threat of multi- and extensively drug-resistant gonorrhoea in Europe. The executive summary:

Gonorrhoea is the second most notified sexually transmitted infection in the European Union and European Economic Area (EU/EEA) after chlamydia. The overall trend between 2008-2017 among 20 of the 28 EU/EEA countries consistently reporting, showed an increase in the number of notified gonorrhoea cases. In addition, over the past decades, Neisseria gonorrhoeae has developed antimicrobial resistance (AMR) to several antimicrobial classes. 

Six years after the initial ECDC Response plan to control and manage the threat of multidrug-resistant gonorrhoea in Europe, the threat of untreatable gonorrhoea remains. ECDC reviewed the response plan and the 2019 update strives to further support EU Member States to develop and implement national strategies and interventions to control the threat of multidrug-resistant and extensively drug-resistant gonorrhoea in a multidisciplinary approach by outlining the suggested public health response to this threat with several vital components. 

Preventing the emergence and spread of AMR in N. gonorrhoeae is just one aspect of gonorrhoea control: as part of comprehensive management strategies including appropriate treatment, diagnostics and testing algorithms (e.g., three-site testing in men who have sex with men), test of cure, notification and treatment of partners, enhanced focus on risk groups and STI prevention measures, including advocating for increased condom use.

Building a tuberculosis-free world: The Lancet Commission on tuberculosis

Via The Lancet: Building a tuberculosis-free world: The Lancet Commission on tuberculosis. The executive summary:

Tuberculosis can be treated, prevented, and cured. Rapid, sustained declines in tuberculosis deaths in many countries during the past 50 years provide compelling evidence that ending the pandemic is feasible. Yet this disease—which has plagued humanity since before recorded history and has killed hundreds of millions of people over the past two centuries—remains a relentless scourge. In 2017, 1·6 million people died from tuberculosis, including 300 000 people with HIV, representing more deaths than any other infectious disease. Moreover, in many parts of the world, drug-resistant forms of tuberculosis threaten struggling control efforts. 

The world can no longer ignore the enormous pall cast by the tuberculosis epidemic. Going forward, the global tuberculosis response must be an inclusive, comprehensive response within the broader sustainable development agenda. No one-size-fits-all approach can succeed. 

In September, 2018, the first-ever UN High-Level Meeting (UNHLM) on tuberculosis resolved to make ending this disease a global priority. Heads of State and government representatives from all UN member states committed to take major steps towards building a tuberculosis-free world, including ambitious goals to treat successfully 40 million people with tuberculosis and to prevent at least 30 million becoming ill between 2018 and 2022, through the provision of tuberculosis preventive treatment.

Achieving these objectives will not be easy. First, many people with tuberculosis, especially the poorest, can neither access nor afford high-quality tuberculosis services. Diagnostic and treatment capacity is not always located where the need is greatest. Consequently, up to 35% of people with tuberculosis disease are not being diagnosed and treated, or made known to national tuberculosis programmes. 

Second, strategies to identify people with active disease in high-risk populations, such as people with HIV, household contacts, migrants, and prisoners, are at best implemented in a piecemeal manner. Furthermore, despite compelling evidence that tuberculosis preventive therapy is life-saving for some among these populations, it is often not offered in high-burden countries. 

Third, tuberculosis research and development is chronically underfunded. Unless urgent steps are taken to substantially increase research and development funding to enable the development of new and more patient-friendly treatment strategies, as well as transformative diagnostics and vaccines, rapid declines in tuberculosis mortality will prove difficult. 

Finally, global efforts to end tuberculosis have been undermined by insufficient political will and financial investments. Economic analysis commissioned for this report show that the value of the benefits of averting a death from tuberculosis exceeds the value of its costs by more than a factor of 3 to 5, and is likely to be considerably more in many settings. Available funding for tuberculosis programmes efforts fall considerably short of what is required. 

Working under the assumption that with smart investments based on sound science, accelerated research and development, and a shared responsibility, we can end tuberculosis within a generation, this Commission set out to answer the question of how tuberculosis high-burden countries and their development partners should target their future investments to ensure that ending tuberculosis is achieved. 

The Commission asserts that to realise the Sustainable Development Goal of reducing tuberculosis mortality by 90% from 2015, as proposed in the WHO's End TB [tuberculosis] Strategy, and to achieve a tuberculosis-free world within a generation, tuberculosis investments must be focused on the five priority areas (see Key messages panel).  

Seizing this moment 

Although the challenges of ending tuberculosis are many, the outlook is encouraging. We have rapid, sensitive diagnostic tools, and the promise of potent tuberculosis treatment strategies in the pipeline. Programmatic innovations, new health technologies, digital solutions, sustained global economic growth, increased commitment to achieve universal health coverage (UHC), and growing political momentum to definitively address tuberculosis, could all make ending the pandemic within a generation more feasible than ever before.

North Korea’s silent health crisis

As Kim and Trump meet in Vietnam (a situation unthinkable three years ago), IRIN reports on North Korea’s silent health crisis. Excerpt:

North Korea is frequently portrayed as an unknowable, impenetrable land. However, a substantial amount of data on health indicators is readily available. While it must be treated with caution – malnutrition figures, for example, don’t include political prisoners languishing in camps – the data can be useful for showing longer-term trends.  

When it comes to the effects of malnutrition, the data shows an improvement in the two decades since the famine ended – but also clear indications of a continuing problem. In 1998, a UNICEF survey found evidence of child stunting – when a child’s height falls considerably below what would be expected at that age. About 62 percent of children younger than seven years of age showed stunted growth, while 60 percent were considered underweight. In 2017, UNICEF’s Multiple Indicator Cluster Survey – drawn from household survey data – reported that roughly 19 percent of children were stunted, while about 9.3 percent were underweight.  

This is clearly an improvement. But one in five children are still considered stunted. The children in the 1998 survey are now in their 20s, many likely with children of their own. Today, the World Food Programme estimates that 10.9 million people are undernourished – about 43 percent of the population. And undernourishment is a common denominator for many of the health problems afflicting North Koreans.  

Undernourishment in pregnant women 

Indicators gauging maternal health in North Korea vary widely. The maternal mortality ratio estimates the proportion of women who die during pregnancy – essentially the risk associated with pregnancy in a given country. World Bank data suggests the maternal mortality ratio in North Korea has fallen steadily since a peak in 1999. However, data from North Korea’s own Central Bureau of Statistics says the maternal mortality ratio has fluctuated and even risen in recent years: from 72 per 100,000 live births, to 62.7 in 2014, then a notable jump to 82 in 2015. 

Even using the World Bank’s more optimistic figures, North Korea’s maternal mortality ratio still hasn’t reached pre-famine levels – estimated at 56 deaths per 100,000 live births in 1992. And it’s still far off the mark set by South Korea, where the ratio is 11.  

Current indicators suggest cause for concern. According to UNICEF, nearly one in three women of reproductive age are undernourished, and nearly one in four are underweight. And the UN agency says it couldn’t distribute nutritional supplements to 95 percent of pregnant and lactating women during a nationwide child health campaign last year, due to funding shortfalls. 

Tuberculosis trouble ahead 

There is a funding crisis for tuberculosis treatment in North Korea, and the disease may be killing people at an increasing rate. World Health Organisation estimates for tuberculosis deaths in North Korea are on the rise: from a low of 42 deaths per 100,000 people in 2015, to 63 in 2017. 

The Global Fund – the donor agency financing treatment for HIV, tuberculosis, and malaria around the world – pulled funding for tuberculosis and malaria programmes last year citing oversight concerns in North Korea’s ”unique operating environment”. The decision was met with worried opinion pieces, open letters, and pleas of concern from the medical community.

With the impact of sanctions and the Global Fund’s withdrawal, there are fears this upward trend may continue. In an open letter published in the British medical journal The Lancet, the director of the Korean American Medical Association, which works on tuberculosis treatment programmes in North Korea, warned that medicine rationing triggered by drugs shortages could fuel the ”rapid creation of drug-resistant TB strains”.

Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests

Via The Lancet Infectious Diseases: Outbreak of multidrug-resistant tuberculosis in South Africa undetected by WHO-endorsed commercial tests: an observational study. The summary:

Background 

Global roll-out of rapid molecular assays is revolutionising the diagnosis of rifampicin resistance, predictive of multidrug-resistance, in tuberculosis. However, 30% of the multidrug-resistant (MDR) strains in an eSwatini study harboured the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes but is missed by commercial molecular assays or scored as susceptible by phenotypic drug-susceptibility testing deployed in South Africa. We evaluated the presence of Ile491Phe among South African tuberculosis isolates reported as isoniazid-monoresistant according to current national testing algorithms. 

Methods 

We screened records of 37 644 Mycobacterium tuberculosis positive cultures from four South African provinces, diagnosed at the National Health Laboratory Service–Dr George Mukhari Tertiary Laboratory, to identify isolates with rifampicin sensitivity and isoniazid resistance according to Xpert MTB/RIF, GenoType MTBDRplus, and BACTEC MGIT 960. Of 1823 isolates that met these criteria, 277 were randomly selected and screened for Ile491Phe with multiplex allele-specific PCR and Sanger sequencing of rpoB. Ile491Phe-positive strains (as well as 17 Ile491Phe-bearing isolates from the eSwatini study) were then tested by Deeplex-MycTB deep sequencing and whole-genome sequencing to evaluate their patterns of extensive resistance, transmission, and evolution. 

Findings 

Ile491Phe was identified in 37 (15%) of 249 samples with valid multiplex allele-specific PCR and sequencing results, thus reclassifying them as MDR. All 37 isolates were additionally identified as genotypically resistant to all first-line drugs by Deeplex-MycTB. Six of the South African isolates harboured four distinct mutations potentially associated with decreased bedaquiline sensitivity. 

Consistent with Deeplex-MycTB genotypic profiles, whole-genome sequencing revealed concurrent silent spread in South Africa of a MDR tuberculosis strain lineage extending from the eSwatini outbreak and at least another independently emerged Ile491Phe-bearing lineage. Whole-genome sequencing further suggested acquisition of mechanisms compensating for the Ile491Phe fitness cost, and of additional bedaquiline resistance following the introduction of this drug in South Africa. 

Interpretation 

A substantial number of MDR tuberculosis cases harbouring the Ile491Phe mutation in the rpoB gene in South Africa are missed by current diagnostic strategies, resulting in ineffective first-line treatment, continued amplification of drug resistance, and concurrent silent spread in the community.

Multiple introductions of multidrug-resistant Candida auris in the USA

Via The Lancet: Multiple introductions and subsequent transmission of multidrug-resistant Candida auris in the USA: a molecular epidemiological survey. The summary:

Background 

Transmission of multidrug-resistant Candida auris infection has been reported in the USA. To better understand its emergence and transmission dynamics and to guide clinical and public health responses, we did a molecular epidemiological investigation of C auris cases in the USA. 

Methods 

In this molecular epidemiological survey, we used whole-genome sequencing to assess the genetic similarity between isolates collected from patients in ten US states (California, Connecticut, Florida, Illinois, Indiana, Maryland, Massachusetts, New Jersey, New York, and Oklahoma) and those identified in several other countries (Colombia, India, Japan, Pakistan, South Africa, South Korea, and Venezuela). We worked with state health departments, who provided us with isolates for sequencing. 

These isolates of C auris were collected during the normal course of clinical care (clinical cases) or as part of contact investigations or point prevalence surveys (screening cases). We integrated data from standardised case report forms and contact investigations, including travel history and epidemiological links (ie, patients that had shared a room or ward with a patient with C auris). Genetic diversity of C auris within a patient, a facility, and a state were evaluated by pairwise differences in single-nucleotide polymorphisms (SNPs). 

Findings 

From May 11, 2013, to Aug 31, 2017, isolates that corresponded to 133 cases (73 clinical cases and 60 screening cases) were collected. Of 73 clinical cases, 66 (90%) cases involved isolates related to south Asian isolates, five (7%) cases were related to South American isolates, one (1%) case to African isolates, and one (1%) case to east Asian isolates. Most (60 [82%]) clinical cases were identified in New York and New Jersey; these isolates, although related to south Asian isolates, were genetically distinct. 

Genomic data corroborated five (7%) clinical cases in which patients probably acquired C auris through health-care exposures abroad. Among clinical and screening cases, the genetic diversity of C auris isolates within a person was similar to that within a facility during an outbreak (median SNP difference three SNPs, range 0–12). 

Interpretation 

Isolates of C auris in the USA were genetically related to those from four global regions, suggesting that C auris was introduced into the USA several times. The five travel-related cases are examples of how introductions can occur. Genetic diversity among isolates from the same patients, health-care facilities, and states indicates that there is local and ongoing transmission.

UN high-level meeting to end tuberculosis disappointing

Via The Lancet: UN High-Level meeting to end tuberculosis disappointing - The Lancet. Excerpt:

A high-level meeting in which a political declaration to end tuberculosis was agreed upon fell short of expectations, experts say. Sophie Cousins reports. 

Tuberculosis experts have labelled the first ever UN High-Level Meeting on the world's biggest infectious disease killer a “disappointment”. On Sept 26, heads of state and political leaders gathered at the UN General Assembly in New York to adopt a political declaration, “United to End Tuberculosis: An Urgent Global Response to a Global Epidemic”, which commits to accelerating action to tackle the disease by 2030. 

There was widespread hope the meeting would represent a historic milestone in the fight against a disease that killed 1·6 million people last year. But fewer than 20 heads of state turned up for the meeting. Leaders from some high-burden tuberculosis countries, including India and Russia, and donors that had promised to help fund the response were missing. 

“I thought this was going to be a historic moment, but I felt nothing historic”, Lucica Ditiu, executive director of the STOP TB Partnership, said. Ditiu said it was “completely unacceptable that no head of state, no head of government, not even one” from the European region, which is battling an epidemic of multidrug-resistance, came to the meeting. 

Sharonann Lynch, tuberculosis and HIV adviser for Médecins Sans Frontières’ Access Campaign, said the turnout for the meeting was “pathetic”. “Tuberculosis once again faces a lack of high-level engagement and attention. It is just a sorry reflection of a lack of political will”, she said. “So much for smashing the status quo on tuberculosis. All we are left with is a bumper sticker slogan that everyone gets to repeat.” 

WHO's Global Tuberculosis Report 2018 was a sobering reminder that global efforts to control the epidemic are not on target to achieve the goal of ending the epidemic by 2030. In 2017, an estimated 10 million people were newly infected with tuberculosis and 4 million remained undiagnosed and untreated. Almost half a million people had developed multidrug-resistant tuberculosis. 

The political declaration includes a commitment to diagnose and treat 40 million people by 2022, including 1·5 million people with drug-resistant tuberculosis, and to provide 30 million people with preventive treatment. They also agreed to increase overall global spending on tuberculosis to at least US$13 billion a year by 2022. WHO estimates a $3·5 billion funding shortfall for tuberculosis control this year; that gap could almost double over the next 5 years. 

While Aaron Oxley, executive director of RESULTS UK, a charity focused on ending extreme poverty, welcomed the declaration, saying it was “meaningful” and “ambitious”, he stressed accountability was critical. “It is ultimately true that, as it stands, it is just a piece of paper”, he said. “Over the last year, the tuberculosis community has mobilised like never before and that does not stop [now]: it accelerates.” 

Ditiu said that, to keep countries accountable, the declaration needs to explicitly state what is expected from each country. “We need to hit ministers and say, ‘this is what you endorsed, this is what it means for you’”, she said. “We need a robust, independent, and transparent way of accountability.”

MSF: Global leaders must make bold commitments at first-ever UN tuberculosis summit

Via MSF.org: Global leaders must make bold commitments at first-ever UN tuberculosis summit. Excerpt:

As global leaders gather for the first-ever United Nations tuberculosis (TB) Summit in New York this week, Médecins Sans Frontières (MSF) called on governments to save more lives by scaling up TB testing and treatment today, and make real commitments to develop more effective and easier-to-use tools to defeat TB tomorrow.  

New global TB figures released last week by the World Health Organization (WHO) show that the response to the world’s deadliest infectious disease remains poor and slow, resulting in the loss of 1.6 million lives in 2017, with 10 million people developing TB. 

Under-diagnosis and under-reporting of TB cases remain major challenges: more than one third of people with TB have remained undiagnosed year on year for the past seven years.  

One of the key reasons for this abysmal TB report card is that governments are slow to scale up the TB testing and treatment tools that are available today. For example, WHO first recommended use of a newer oral drug bedaquiline for treatment of drug-resistant TB in 2013. 

However, uptake of bedaquiline and other newer drugs remains very slow, with the medicines remaining inaccessible to almost 90 percent of people who could have benefitted from them in 2017. As WHO just recommended bedaquiline now be used as the backbone of treatment for all people with multidrug-resistant TB— instead of medicines that need to be injected—governments must act rapidly to expand access to safer, more effective, injection-free treatment regimens. 

“We have seen too many senseless and painful deaths in countries where we work, because people are still not getting access to today’s best-available TB tests and treatments that are more effective and cause fewer severe side effects,” said Dr Gabriella Ferlazzo, TB/HIV advisor with MSF’s Southern Africa Medical Unit. 

“On 26 September, world leaders have a historic opportunity to turn the tide on the global TB epidemic by making firm commitments for rapid scale-up of new tools for effective diagnosis and treatment of the disease.”   

For decades, there has been chronic under-funding of research and development (R&D) for TB tests and drugs. Most tools available to treat TB have not changed much since the 1940s, and only two new TB drugs have been developed in the last 50 years. Today, only 25 percent of people with multidrug-resistant TB (MDR-TB) are properly diagnosed and treated. 

People “lucky” enough to start treatment have to go through a two-year-long painful process, involving nearly 170 injections and more than 12,000 pills, both of which can cause harsh side effects including deafness, psychosis and even suicide. Cure rates for multidrug-resistant TB are abysmal, as only about 55 percent of people – barely half – who receive treatment are cured. 

MMWR: Multidrug-resistant Campylobacter jejuni outbreak linked to puppy exposure — United States, 2016–2018

Via MMWR: Multidrug-Resistant Campylobacter jejuni Outbreak Linked to Puppy Exposure — United States, 2016–2018. The summary:

What is already known about this topic?  

Dogs, especially puppies, are a known source of sporadic Campylobacter infections in humans, but are uncommonly reported to cause outbreaks. 

What is added by this report?  

Investigation of a multistate, multidrug-resistant outbreak of Campylobacter jejuni infections implicated puppies from breeders and distributors sold through pet stores as the outbreak source. Outbreak strains were resistant to all antibiotics commonly used to treat Campylobacter infections.  

What are the implications for public health practice? Consumers, employees, and clinicians should be aware of the risk for disease transmission from puppies, including the possibility of exposure to multidrug-resistant pathogens. Greater adherence to implementation of antibiotic stewardship practices in the commercial dog industry might be needed.

WHO Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB)

WHO has published Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB).

Major improvement in treatment outcomes and quality of life of patients with multidrug-resistant tuberculosis (MDR-TB) are expected, following key changes in MDR-TB treatment announced by WHO in the Rapid Communication. 

The first important change is a new priority ranking of the available medicines for MDR-TB treatment, based on a careful balance between expected benefits and harms. Treatment success for MDR-TB is currently low in many countries. This could be increased by improving access to the highest-ranked medicines for all patients with MDR-TB.  

The WHO rapid communication aims to encourage and prepare countries to implement the upcoming new consolidated, updated and more detailed WHO policy guidelines on MDR-TB treatment which will be released later this year. 

WHO is also establishing a multi-stakeholder Task Force to coordinate support to national TB programmes in their rapid transition to the key changes envisaged.

Effect of bedaquiline on mortality in South African patients with MDR-TB

Via The Lancet Respiratory Medicine: Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. The summary:

Background 

Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.  

Methods 

In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). 

We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. 

We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment. 

Findings 

24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. 

Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28–0·46) and extensively drug-resistant tuberculosis (0·26, 0·18–0·38) compared with standard regimens. 

Interpretation 

Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen.