The Extraordinary Prof Coomarasamy Scores a Hat-trick!

To publish three papers in the New England Journal of Medicine in as many months is something out of the ordinary. Yet this is precisely what Prof Coomarasamy and his colleagues achieved between March and May of this year.[1-3]

The first paper was a randomised trial of prophylactic antibiotics when a woman has an evacuation of the uterus for miscarriage.[1] Over 3,400 people were enrolled across Pakistan, Uganda, Tanzania and Malawi. About one woman in 20 developed some type of pelvic infection, but there was no difference according to treatment group. However, the point estimate was in favour of antibiotics, with a one percentage point difference. Since it is known that prophylactic antibiotics are effective across surgery in general,[4] this failure to find evidence of effectiveness should not be taken as evidence of no effectiveness. The suspicion that the treatment might have been effective is increased by the finding that antibiotics were associated with a significantly lower rate of infection, based on the strict CDC definition. Accordingly, the Bayesian CLAHRC WM Director recommends antibiotics in this situation.

The second trial compared the use of thyroxine versus placebo to reduce the risk of miscarriage in people who have thyroid antibodies, but who are euthyroid.[2] Despite the poor rationale for the treatment to work in those who have normal thyroid levels, some previous studies had shown this treatment to be effective. This, rather than a sound theory, was the rationale for the trial. Not surprisingly, the treatment was ineffective (okay, not effective) in nearly 1,000 woman randomised.

The last trial also evaluated hormonal substitution: in this case progesterone for people with a threatened miscarriage.[3] A drop in progesterone levels is theoretically more likely to be the result, rather than the cause, of miscarriage. However, yet again, previous trials had suggested that progesterone therapy can avert miscarriage. And again, the result was null on nearly 4,200 women recruited at 48 hospitals in the UK.

Congratulations to Prof Coomarasamy and his team on these three important studies.

— Richard Lilford, CLAHRC WM Director

References:

1. Lissauer D, Wilson A, Hewitt CA, et al. A Randomized Trial of Prophylactic Antibiotics for Miscarriage Surgery. N Engl J Med. 2019; 380: 1012-21.
2. Dhillon-Smith RK, Middleton LJ, Sunner KK, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med. 2019; 380: 1316-25.
3. Coomarasamy A, Devall AJ, Cheed V, et al. A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy. N Engl J Med. 2019; 380: 1815-24.
4. Bowater RJ, Stirling SA, Lilford RJ. Is antibiotic prophylaxis in surgery a generally effective intervention? Testing a generic hypothesis over a set of meta-analyses. Ann Surg. 2009; 249(4): 551-6.

Examining Quality of TB Care with Standardised Patients

Kwan and colleagues have recently published another study to add to their growing portfolio of research on the use of standardised patients (SP) (i.e., actors trained to act as a real patient and portray a case) to examine the quality of tuberculosis (TB) care in India.[1] This interesting paper builds on their prior work, some of which we have discussed in earlier editions of this blog.[2]

TB is a significant problem in India. It accounts for a quarter of the world’s estimated 10.4 million new cases of TB annually, and nearly a third of the 1.7 million yearly TB deaths. The quality of healthcare provision in India’s private sector – the first point of contact for the bulk of symptomatic TB patients – is generally accepted to be suboptimal and highly variable.

This impressive study involved 2,652 SP-provider interactions across 1,203 health facilities and 1,288 provider practices in two economically disparate Indian cities (Mumbai and Patna) with a high prevalence of cases of TB. It focused on healthcare providers both with and without formal medical training, and was covertly nested within a Government of India initiated TB management improvement programme. The authors trained 24 local actors (seven female and 17 male) to portray four scenarios representing various stages of diagnostic and disease progression of TB. Over a nine month period, SPs undertook incognito visits to providers – with measures in place to protect against detection. Within two-hours of each visit a field researcher administered exit questionnaires to SPs to record details of the interaction. The main outcome of interest in this study was case-specific correct management based on local clinical guidelines for the management of TB.

The key findings were that:

• Only 25% of SP-provider interactions resulted in standards-compliant care.
• Only 35% of cases were correctly managed and of these, 53% of providers ordered a chest X-ray, 36% referred the SP for further care (roughly equal split of referrals to private and public sector providers), and 31% ordered a microbiological test for diagnosis – a relatively infrequent occurrence across all case scenarios.
• Medicines (mostly antibiotics) were very frequently prescribed or dispensed – the average rate was three per interaction.
• Rather unsurprisingly, yet reassuringly, medically trained providers were almost three times more likely than non-medically trained providers to correctly manage cases, ask for chest X-ray and/or sputum tests, and initiate anti-TB treatment.
• Differences in case management for medically and non-medically trained providers between Mumbai and Patna were minimal.

However, the important take-home message is that, in spite of providing relatively higher-quality care, medically trained providers still only correctly managed 54% of interactions, and were more likely than others to prescribe unnecessary or harmful antibiotics, which in a global epidemic of antibiotic resistance, is a particularly worrying result.

A key strength of this study is that it provided representative data on actual provider behaviour, thus addressing the widely acknowledged ‘know-do’ gap, though it also reiterates two important and recurrent considerations for the use of SPs in research studies:

1. SPs are most useful for first-visits and have not yet been used in repeat visits. But is it reasonable to assume that quality of care may be better at a follow-up visit? This is an issue worthy of investigation in future work.
2. Should we be asking for prior consent from participating providers? A continuing issue of contention, particularly relevant to the use of SPs in real-life (not educational) settings.

— Navneet Aujla, Research Fellow

Reference:

1. Kwan A, Daniels B, Saria V, et al.Variations in the quality of tuberculosis care in urban India: A cross-sectional, standardized patient study in two cities. PLoS Med. 2018; 15(9): e1002653.
2. Lilford RJ. Private Consultations More Effective Than Public Provision in Rural India. NIHR CLAHRC West Midlands News Blog. 23 June 2017.

People Designated as Allergic to Penicillin Have an Increased Incidence of Clostridium Difficile Diarrhoea

This hypothesis was tested out by a group of researchers from Harvard using the THIN Database from England [1]; a nice example of the merits of making the data collected in one country available to researchers in another.

The hypothesis that these investigators are examining is obvious: they want to see whether the substitution of broad spectrum antibiotics for penicillin and its analogues, leads to a detectable increase in Clostridium difficile diarrhoea. This is an important investigation, since only 5% of people labelled as allergic, have any real risk of an immediate reaction to penicillin.

This study was based on over 64,000 people with putative penicillin allergy and nearly 200,000 matched comparators. Over a mean of six years of follow up, an approximately 70% increase in risk of C. difficile was observed among patients labelled allergic to penicillin. The authors suggest routine testing for penicillin allergy, but I think this would be logistically hard to achieve, and recommend more careful history taking when making the original diagnosis. Other measures to reduce the incidence of Clostridium difficile diarrhoea, such as more circumspect prescription of fluoroquinolones, should also be pursued.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Blumenthal KG, Lu N, Zhang Y, et al. Risk of meticillin resistant Staphylococcus aureus and Clostridium difficile in patients with a documented penicillin allergy: population based matched cohort study. BMJ. 2018; 361: k2400.

Widespread Use of Antibiotics to Reduce Child Mortality

As discussed in our previous News Blog,[1] the rise in antibiotic resistance is a worrying situation, and it is widely recommended to limit the prescription of antibiotics to patients who are confirmed to have a treatable bacterial infection. However, a recent trial in three sub-Saharan African countries did the exact opposite with a mass distribution of azithromycin, a broad-spectrum antibiotic, to children under five with the aim of reducing child mortality.[2] This was a cluster-randomised trial of around 190,000 children in 1,533 communities of Malawi, Niger and Tanzania who were assigned to receive four biannual doses of antibiotic or a placebo. Overall, the mortality rate was 14.6 deaths per 1,000 person-years in areas that received the antibiotic, compared to 16.5 deaths in communities that received the placebo, while mortality was also 13.5% lower (95% confidence interval, 6.7-19.8) (p<0.001). The effect was greatest in the youngest sub-group of children, those aged between one and five months, with the authors estimating that one in four expected deaths were prevented due to administration of the antibiotic. There were no differences in serious adverse events within a week of administration. If this strategy was to be more widely rolled out, one approach to combat resistance developing would be to limit it to the populations most in need and only for a short time.[3]

— Peter Chilton, Research Fellow

References:

1. Chilton PJ. Non-Antibiotic Medicines May Increase Antibiotic Resistance. NIHR CLAHRC West Midlands News Blog. 18 May 2018.
2. Keenan JD, Bailey RL, West SK, Arzika AM, for the MORDOR Study Group. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. New Engl J Med. 2018; 378: 1583-92.
3. Maxmen A. Giving at-risk children pre-emptive antibiotics reduces deaths. Nature. 25 April 2018.

Non-Antibiotic Medicines May Increase Antibiotic Resistance

Alexander Fleming predicted the emergence of antibiotic resistance, and he was soon proved right. The increase in antibiotic resistant bacteria has been at least partially due to the over prescribing of antibiotics by GPs, healthcare centres, etc.[1] Steps have been taken in­­ recent years to combat this,[2] though a recent database study by Smieszek, et al. estimated that between 8.8%-23.1% of antibiotic prescriptions in English primary care were inappropriate,[3] and the situation is much worse in low- and middle-income countries.[4] Now, a study published in Nature by staff from the European Molecular Biology Laboratory has found potential risk from prescribing non-antibiotics.[5]

Previous research has found that medication that targets human cells, as opposed to microbes (for example, anti-diabetics, proton pump inhibitors, non-steroidal anti-inflammatory drugs) may alter the composition of the gut flora. In order to determine the extent of such effects the authors tested over 1,000 drugs against 40 human gut bacterial strains. They found that 24% of those with human targets inhibited the growth of at least one of the strains (and 5% affected at least ten strains). While this could offer new avenues for future drug-therapy research and personalised medicine, the authors also found strong correlation between resistance to antibiotics and to drugs that target human cells, likely due to common mechanisms conferring resistance. This means there is a potential risk of non-antibiotics promoting antibiotic resistance in some bacteria – a concern with the large amount of non-antibiotics taken on a regular basis by a large number of people.

— Peter Chilton, Research Fellow

References:

1. Van Boeckel TP, Gandra S, Ashok A, Caudron Q, Grenfell BT, Levin SA, Laxminarayan R. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis. 2014; 14(8): 742-50.
2. Hoffman SJ, Outterson K, Røttingen J-A, et al. An international legal framework to address antimicrobial resistance. Bull World Health Organ. 2015; 93(2): 66.
3. Smieszek T, Pouwels KB, Dolk FCK, et al. Potential for reducing inappropriate antibiotic prescribing in English primary care. J Antimicrobial Chemo. 2018; 73(s2): ii36-43.
4. Das J, Chowdhury A, Hussam R, Banerjee AV. The impact of training informal health care providers in India: A randomized controlled trial. Science. 2016; 354: aaf7384.
5. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555: 623-8.

Antibiotics Work!

Yes, an RCT of antibiotics vs. an anti-inflammatory drug in people with lower urinary tract infection shows clearly that the antibiotic is superior in reducing (in fact halving) the mean duration of symptoms.[1] I have worried before [2] about long-term effects of withholding antibiotics in conditions often caused by bacteria – quinsy in throat infections, for example. In this trial the risk of pyelonephritis (kidney infection) was higher in the group from whom antibiotics were withheld. Appropriate targeting of antibiotics is important. And I prefer high dose, short duration therapy regimes.[3] [4]

— Richard Lilford, CLAHRC WM Director

References:

1. Kronenberg A, Bütikofer L, Odutayo A, Mühlemann K, da Costa BR, Battaglia M, Meli DN, Frey P, Limacher A, Reichenbach S, Jüni P. Symptomatic treatment of uncomplicated lower urinary tract infections in the ambulatory setting: randomised, double blind trial. 2017; 359 :j478.
2. Lilford RJ. Protocol to Test Hypothesis That Streptococcal Infections and Their Sequelae Have Risen in Incidence Over the Last 14 Years in England. NIHR CLAHRC West Midlands News Blog. 13 January 2017.
3. Lilford RJ. Not Taking a Full Course of Antibiotics. NIHR CLAHRC West Midlands News Blog. 29 September 2017.
4. Lilford RJ. More Evidence for Short Doses of Antibiotics in Infection. NIHR CLAHRC West Midlands News Blog. 5 June 2015.

Not Taking a Full Course of Antibiotics

The Academic edition of the BMJ comes out once a month; readers may have noticed that one or more BMJ articles feature in alternate News Blogs. The most recent issue of the BMJ had less papers that caught my eye than most. There was lots of worthy stuff. For example, age-specific dementia incidence is declining slightly,[1] antidepressants may very slightly increase the risk of autism if taken during pregnancy,[2] specialist palliative care has rather small effects on quality of life,[3] exercise and diet reduce the risk of high blood pressure in women who had high blood pressure in pregnancy.[4] There was also an excellent article on the precision of cluster randomised trials by CLAHRC WM collaborator Karla Hemming.[5] But the article that really caught my eye was a commentary on the importance of completing a full course of antibiotics as prescribed.[6]

Of course, we always love articles that confirm our prior beliefs. I have always thought that insisting that people take a ‘full course’ of antibiotics to reduce resistance is illogical. Prolonging exposure of the bacterial population to the antibiotic is likely to increase the chance for selection to take place. And that is exactly what this study confirms. Apparently the idea that it was important to take the full course of treatment was based on Albert Alexander’s Staphylococcal sepsis, which re-established itself when Howard Florey’s penicillin ran out.[7] However, the wisdom of continuing antibiotics until the infection is quelled somehow became translated into instructions to finish the course even if infection is no longer a threat. Remember, genetic mutations arise spontaneously and are only selected for when the antibiotic is present in the environment. It follows that the shortest course of antibiotics compatible with effective treatment should be used. And, of course, resistance does not just appear among the organisms causing the infection, but among all the organisms carried in the patient’s body, some of which may go on to infect another person. The argument against continuing to take antibiotics once the threat has passed is therefore unequivocal. It may be necessary to continue antibiotic treatment to prevent a relapse, as was the case for the hapless Alexander, and middle ear infections have a tendency to relapse, but we should not insist on taking a full course simply to prevent antibiotic resistance; the opposite is the case.

— Richard Lilford, CLAHRC WM Director

References:

1. Ahmadi-Abhari S, Guzman-Castillo M, Bandosz P, et al. Temporal trend in dementia incidence since 2002 and projections for prevalence in England and Wales to 2040: modelling study. BMJ. 2017; 358: j2856.
2. Rai D, Lee BK, Dalman C, et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017; 358: j2811.
3. Gaerner J, Siemens W, Meerpohl JJ, et al. Effect of specialist palliative care services on quality of life in adults with advanced incurable illness in hospital, hospice, or community settings: systematic review and meta-analysis. BMJ. 2017; 357: j2925.
4. The International Weight Management in Pregnancy Collaborative Group. Effect of diet and physical activity based interventions in pregnancy on gestational weight gain and pregnancy outcomes: meta-analysis of individual participant data from randomised trials. BMJ. 2017; 358: j3119.
5. Hemming K, Eldridge S, Forbes G, Weijer C, Taljaard M. How to design efficient cluster randomised trials. BMJ. 2017; 358: j3064.
6. Llewelyn M, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ. 2017; 358: j3418.
7. Abraham EP, Chain E, Fletcher CM, et al. Further observations on penicillin. Lancet. 1941; 358: 177-89.

A Novel Drug for Tuberculosis

Once rampant across the globe Tuberculosis has been brought under control, first by improved hygiene standards, and then antibiotic drugs, such as isoniazid and rifampicin, developed in the 1950s and 1960s. However, it remains one of the top 10 causes of death across the world, infecting 10.4 million people and killing 1.8 million in 2015, the vast majority (95%) in low- and middle-income countries.[1] Further, there has been a rise of TB strains that are resistant to antibiotics – around 480,000 people developed multi-drug resistant TB (MDR-TB) in 2015.[1] Of these, only 52% were successfully treated by second-line treatment options, such as extensive chemotherapy. More worryingly, there has been a rise in cases developing extensive drug resistance (XDR-TB), which has very limited treatment options. One of the United Nation’s Sustainable Development Goals is to end the TB epidemic by 2030, but to do this new antibiotics are needed to which no resistance has developed.

University of Warwick researcher Gregory Challis, together with Eshwar Mahenthiralingam and colleagues, recently discovered a promising candidate – gladiolin. [2] Bacteria belonging to the genus Burkholderia are able to thrive in a diverse range of environments thanks to their ability to produce potent antibiotics to remove any competition. Researchers were able to isolate gladiolin by screening one such strain, B. gladioli, that was taken from a child with cystic fibrosis. Gladiolin works by inhibiting RNA polymerase (a validated drug target in TB), has significantly improved chemical stability compared to structurally similar antibiotics, and has low cytotoxicity in mammals. Further research found that while gladiolin was less effective (compared to isoniazid and rifampicin) against strains of TB with no resistance, it had good activity against several strains of TB that were resistant to isoniazid and rifampicin. It is hoped that gladiolin will be the starting point for developing new drugs that can tackle MDR-TB and XDR-TB.

— Peter Chilton, Research Fellow

References:

1. World Health Organization. Tuberculosis Fact Sheet. 2017.
2. Song L, Jenner M, Masschelein J, et al. Discovery and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity against Mycobacterium tuberculosis. J Am Chem Soc. 2017; 139(23): 7974-81.

The Brain Speaketh Unto the Gut and the Gut Answereth Back

In the previous News Blog I mentioned the hypothesis that an altered gut microbiome may trigger chronic fatigue syndrome.[1] I promised more on the topic. Many years ago I chaired the Scientific Advisory Committee for the MRC Oracle study. This was a study of antibiotics versus no antibiotics to prevent preterm labour.[2] There were no differences in short-term outcomes in children of the antibiotic versus control mothers. But CLAHRC WM associate Sara Kenyon and her colleagues followed the children up to the age of seven. The results show markedly higher levels of cerebral palsy in the intervention (antibiotic) group over the control (no antibiotics) group, and in one of the two antibiotics used the risk of other functional impairments was also increased.[3] I was also inclined to pass this off as a chance finding – type 1 error. Now I am not so sure – recent evidence in Nature [4] shows that antibiotics in baby mice cause changes on their frontal cortices, affect the blood-brain barrier, and alter behaviour. These changes are partially preventable by probiotic administration. If maternal antibiotics are bad for the baby brain, then presumably so is neonatal antibiotic administration. It would be interesting to follow up neonates of given gestational age, mass and clinical condition to compare outcomes in those given antibiotics and non-antibiotics. Yes, I know it will be confounded by indication for antibiotics, so a null result would be more informative than a positive result.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Biological Underpinnings of Chronic Fatigue? NIHR CLAHRC West Midlands News Blog. 21 April 2017.
2. Kenyon S, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet. 2001; 357: 979-88.
3. Kenyon S, Pike K, Jones DR, Brocklehurst P, Marlow N, Salt A, Taylor DJ. Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial. Lancet. 2008; 372: 1319-27.
4. Leclercq S, Mian FM, Stanisz AM, et al. Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior. Nat Commun. 2017; 8: 15062.

Clinical and Epidemic Outcomes from Implementation of Hospital-Based Antimicrobial Stewardship Programmes (ASPs)

The poor authors of this study had to read 24,917 citations to locate 26 studies with pre- and post-implementation comparisons.[1] The mean effect across these 26 ASPs was a 19% reduction in total antimicrobial consumption, while there was a 27% reduction in use of ‘restricted’ antibiotic agents, and an 18.5% reduction in use of broad-spectrum antibiotics. Overall hospital costs decreased by no less than 34% (mainly due to a 9% reduction in length of stay). There was a reduction in infections with resistant organisms, but no overall reduction in infection related adverse events. Of course, the interventions varied in nature and there was no attempt to classify them (say by type and intensity of intervention) and analyse the results accordingly. The study designs are generally weak, not controlling for temporal trends. The health economics is short-term and (for understandable reasons) the potential benefits of a contingent decrease in antimicrobial resistance were not modelled.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Karanika S, Paudel S, Grigoras C, Kalbasi A, Mylonakis E. Systematic Review and Meta-analysis of Clinical and Economic Outcomes from the Implementation of Hospital-Based Antimicrobial Stewardship Programs. Antimicrob Agents Chemother. 2016; 60(8): 4840-52