Tag Archives: Antibiotics

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

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

[DRAFT 1: PRE FIRST LOOK AT DATA: 13 Jan 2017]

Rationale

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.

Methods

  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)
Mastoiditis
Cholesteatoma
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

Age
Sex
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.

References:

  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

Reference:

  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

Reference:

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

More Evidence for Short Doses of Antibiotics in Infection

The CLAHRC WM Director was always taught at Medical School to provide long courses of antibiotics (7–10 days) and try to maximise compliance throughout. This was thought to reduce the emergence of resistance. Hedrick et al.[1] add to the evidence that short courses are less likely to result in antimicrobial resistance. So what’s best for the patient – a fixed short course or wait until the patient ‘responds’? Surprisingly, no difference in outcome was observed in Hedrick’s study. This would explain why the physiological response to infection appears to outlast the effective phase for antibiotic effectiveness. Most of the symptoms of infection result from the immune response to infection, not the infection itself. The CLAHRC WM Director hypothesises that persistence of symptoms beyond the effective phase of antibiotic use is caused by the bodies ‘mopping up’ exercise, where the immune system is eradicating dead or damaged bacteria.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Hedrick TL, Evans HL, Smoth RL, et al. Can we define the ideal duration of antibiotic therapy? Surg Infect. 2006; 7(5): 419-432.

Routine Antibiotics after Stroke

A multiple-indication review conducted by the CLAHRC WM Director showed that prophylactic antibiotics effectively reduced post-operative infections, with an effect size in relative risk ratio terms that was independent of the type of surgery.[1] A recent paper [2] confirmed that prophylaxis also reduced risk of infection after acute stroke. However, it did not improve functional outcomes, length of stay, or mortality, and the authors do not recommend routine use.

— Richard Lilford, CLAHRC WM Director

References:

  1. 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.
  2. Westendorp WF, Vermeij JD, Zock E, et al. The Preventive Antibiotics in Stroke Study (PASS): a pragmatic randomised open-label masked endpoint clinical trial. Lancet. 2015. [ePub].

Antibiotic resistance – a technical solution after all?

Killing bacteria outside of the body is a relatively simple and straightforward process – denature their proteins by heat or chemicals and thereby kill them. The bacteria can’t get resistant since the denaturalisation process is non-selective, targeting all proteins. Such an approach is not possible once the bacteria have colonized the body, however, since it would harm or kill the host. It is therefore necessary to find a (relatively) specific aspect of microbial metabolism and attack that. However, life-forms can continue using alternative pathways for which the anti-microbial selects if used over a long enough period – a living example of evolution. The obvious place to hit a bacterium is the cell wall, since there is no equivalent in mammalian cells, which are surrounded only by a membrane. Bacteria, however, find a way around this solution, producing neutralizing enzymes to destroy the active part of the antibiotic. So what we need is a molecule that attacks the cell wall and which lies outside the range of neutralizing proteins afforded by nature. A recent report suggests that just such a compound may have been discovered.[1] This compound, termed teixobactin, has been discovered in a soil bacterium, Eleftheria terrae, which cannot be cultured by traditional means. This compound is bactericidal against Gram-positive bacteria (such as MRSA, VRSA and C. difficile) and it has proven impossible to generate resistance in the laboratory – at least so far!

Further, the method used to obtain texiobactin may also be able to help us find other bactericidal compounds. Conventional laboratory methods of growing microbes from soil kill off 99%, but the authors followed a different strategy using “isolation cells” that protect the bacterium sample with a semi-permeable membrane and allow it to grow in its natural environment prior to plating. This method could potentially allow us to recover 50% of soil bacteria, and hence potentially identify many more new antibiotics.

— Richard Lilford, CLAHRC WM Director
— Peter Chilton, Research Fellow

Reference:

  1. Ling LL, Schneider T, Peoples AJ, et al. A new antibiotic kills pathogens without detectable resistance. Nature. 2015; 517(7535): 455-9.