Tag Archives: Antibiotics

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


  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


  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


  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


  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


  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


  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


  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

Protocol to Test Hypothesis That Streptococcal Infections and Their Sequelae Have Risen in Incidence Over the Last 14 Years in England



Streptococcal respiratory tract disease was a scourge of high-income countries (HICs) in the pre-antibiotic era. The sequelae were local (e.g. peritonsillar abscesses [Quinsy], mastoiditis, and even brain abscesses) or distant (rheumatic fever, childhood glomerulonephritis). The incidence of these diseases has reduced dramatically in HICs in the last 50 years, at least in part as a result of (liberal) use of antibiotics. However, strong pressure has been placed on doctors to reduce antibiotic prescribing. The evidence from RCTs has shown that the mean duration of diseases, such as tonsillitis, sinusitis and acute middle ear infection, is only slightly (about 20%) reduced by antibiotic therapy. The actual drop in prescriptions has been modest.[1] However, we plan to establish a trend line, and then continue to observe the incidence so that any upturn in serious disease can be detected early. We shall therefore observe the trends in craniofacial disorders that are often the result of local spread of Streptococcal infections and also the above mentioned autoimmune diseases. We will also track a condition that may tell us something about the underlying ecology of Streptococcal infections – scarlet fever. We will attempt to obtain data on actual antibiotic prescribing (overall and for the above infections) by year. A previous study based on primary care records [2 found that general practices with the greatest reductions in antibiotic prescribing experienced an increase in peritonsillar abscesses compared to baseline control patients. They did not examine for autoimmune disease.


  1. Database: We will search the Hospital Episode Statistics database for England, which contains information on all NHS-funded admissions to hospitals in England. All admissions are given ICD 10 (International Classification of Disease, 10th Revision) Diagnosis Codes and OPCS-4 (Office of Population Censuses and Surveys Classification of Interventions and Procedures) Procedure Codes. The HES database is linked to the Indices of Multiple Deprivation database and we will thus be able to obtain the socioeconomic status of patients.
  2. Date: 1st January 2001 to 31st December 2015 [to be confirmed]
  3. Search terms: See table 1.

Table 1: Disease Classes and Specific Search Terms

Broad Disease Type Disease Search terms
[to be completed]
Local spread Peritonsillar abscess (quinsy)
Temporal lobe abscess
Lemierre’s syndrome
Autoimmune Glomerulonephritis (under age 16)
Rheumatic fever
Scarlet fever

If a patient on a single admission has more than one disease, then the most serious condition (lowest on the list) will be recorded. Patients may have more than one admission.

  1. Additional information collected: See table 2.

Table 2: Additional Information to be Collected from Each Patient

Social class
Urban / rural residence
Number of admissions before first admission for one of the above diseases
  1. Analysis:
    We shall produce descriptive statistics for the mean values for numbers and proportions of admissions by disease and by disease category for age, sex, social class, and residence. At this stage we do not plan to use number of previous admissions in the analysis. We shall carry out the following analyses in pursuit of our hypothesis:

    1. We shall plot the number of cases of each of the above conditions by year. We shall also plot proportions of all admissions by condition.
    2. We shall make similar plots for people 16 and below, and for older people.
    3. We will group conditions into: 1) local spread, 2) auto-immune, and 3) scarlet fever for analysis.
    4. We shall generate age-standardised incidence rates and test whether there is a trend over time using joinpoint regression models. We will also look at age-specific incidence rates in a similar manner.

If there is a trend, we shall compare this across urban and rural residence, using the ONS classification. Likewise we will examine trends by the lowest social class versus all other social classes.


  1. Peterson I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC. Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database. BMJ. 2007; 335: 982.
  2. Gulliford MC, Moore MV, Little P, Hay AD, Fox R, Prevost AT, Juszczyk D, Charlton J, Ashworth M. Safety of reduced antibiotic prescribing for self limiting respiratory tract infections in primary care: cohort study using electronic health records. BMJ. 2016; 354: i3410.

Boosting the Body’s Natural Immunity

The Professor of Microbiology at St Mary’s Hospital in the years leading up to World War 2 was Sir Almroth Wright. He thought that the quest for antimicrobial drugs was doomed and instead promoted the search for methods to boost the natural immunity of the body. Unfortunately he worked in the same department as Alexander Fleming, so after the discovery of penicillin the students nicknamed him Sir Almost Right! But was he only almost right? Time would seem to vindicate his approach, at least with respect to tuberculosis (TB) according to a recent article in Nature Reviews.[1] TB organisms are developing resistance, TB drugs may interact with anti-HIV treatment (Immune Reconstitution Inflammatory Syndrome), and prolonged maintenance of therapy is required. Many treatments to fight the disease by boosting the body’s immune response are now in trials. These include cell therapies, such as mesenchymal stem cell treatment, and repurposed drugs, such as vitamin D (that induces release of anti-microbial peptides) and the anti-cancer kinase inhibitor imatinib, and therapeutic vaccines designed specifically to augment immunity.

— Richard Lilford, CLAHRC WM Director


  1. Zumla A, Chakaya J, Hoelscher M, et al. Towards host-directed therapies for tuberculosis. Nat Rev Drug Discov. 2015; 14(8):511-2.

Emergence of Antimicrobial Resistance is Much Greater in Low- than High-Income Countries

This recent article in Science [1] gives five evidence-based reasons for greater emergence of, and more devastating consequences from, antibiotic resistance in low-income countries (LICs) compared to higher income countries:

  1. LICs harbour a higher rate of extremely virulent organisms, such as those responsible for typhoid fever and tuberculosis.
  2. Antimicrobials are (even) less carefully regulated and are frequently available ‘over the counter’.
  3. Treatment for established infection is more often delayed and access to supportive care for life-threatening infections is less widely available.
  4. Laboratory testing for the infectious agent is less widely available and therefore ‘syndromal’ treatment based on suspicion, rather than confirmation of a bacterial cause for ill health, is understandably widespread.
  5. Routine dosing of animals to improve yields is more widespread.

Of course, increasing resistance to antibiotics in LICs impacts on high-income countries, and the article shows how molecular tracking of microbial genetics has enabled the dissemination of resistance genes to be mapped across the world.

The CLAHRC WM Director thinks that new molecular genetic techniques will help target antibiotics at the correct diagnosis, and also help in controlling the spread of resistant organisms. The technology is becoming ever cheaper, as discussed in a previous blog.

— Richard Lilford, CLAHRC WM Director


  1. Baker S. A return to the pre-antimicrobial era? Science. 2015; 347(6226):1064-6.