Antimicrobial resistance - a global public health threat

"Proper infection control practices and antimicrobial stewardship will be important to address this emerging threat" is the conclusion of a new publication from Sub-Saharan Africa on trends and reasons why resistance to antibiotics is becoming an increasing international problem.

The study, just published in the latest issue of the American Journal of Tropical Medicine and Hygiene, looked at data collected over a 5 year period on sensitivity of bacterial cultures to a wide range of WHO essential list as well as newer antibiotic medicines.

The data were collected in Kigali, Rwanda, at King Faisal Hospital, a major teaching and referral hospital for patients from throughout
Rwanda and from neighbouring countries.

The research team comprised international researchers from the USA (Yale AIDS Programme and the Department of Public Health, Philadelphia), the UK (Fellowship of Postgraduate Medicine, London) and SMBT Institute of Medical Science and Research Center in Nashik, India, in collaboration with clinicians from the King Faisal Hospital in Kigali, Rwanda.

"Differences in antimicrobial susceptibility between the first and fifth year of the study for each bacterial species was assessed using 2 test. Of 5,296 isolates collected, 46.7% were Escherichia coli, 18.4% were Klebsiella spp., 5.9% were Acinetobacter spp., 7.1% were Pseudomonas spp.,
11.7% were Staphylococcus aureus, and 10.3% were Enterococcus spp. Colistin and imipenem had greatest activity against gram-negative bacteria. 
Acinetobacter spp. showed the greatest resistance profile to antimicrobials tested, relative to other gram-negative bacteria. Vancomycin retained excellent activity against S. aureus and Enterococcus species (average susceptibility was 100% and 99.4%, respectively). 
Trend analysis determined that resistance to imipenem increased significantly among Klebsiella, E. coli, Pseudomonas, and Acinetobacter isolates; there was also rising resistance to colistin among E. coli and Pseudomonas species. 
Only E. coli demonstrated increased resistance to gentamicin. For gram-positive pathogens, vancomycin susceptibility increased over time for Enterococcus species, but was unchanged for S. aureus. Our data suggest that resistance to imipenem and colistin are rising among gram-negative bacteria in Rwanda."

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Health risks in the Sierra Nevada?

@HealthMed Every year millions of people visit beautiful Yosemite and Lake Tahoe in the Sierra Nevada of the Western USA. The individual risk of contracting a serious infection is low, however there are several rare but important public health risks. These range from minor nuisance from irritating bites by ‘no-see-ums’ to a range of serious infections.

Yosemite National Park

While visiting there in mid-August, there were reports in the US press of 2 deaths from hantavirus infection, attributed to contact in the Yosemite National Park area with deer-mice as the carrier. There are also notices posted at other beauty spots in the Sierra Nevada not to handle small animals; ground squirrels and other small mammals were reported to harbour plague; ‘no-see-ums’ to be vectors for West Nile virus infection (around half those affected developing an encephalitis syndrome); and ticks to carry risk of acquiring Lyme disease or the protozoal infection, babesiosis. The Centers for Disease Control in Atlanta report that these infections are rare, however urgent treatment for infected individuals may be needed, with public health measures important.

In practice, in mid-August, whether or not due to insect spray provided by a friendly bed and breakfast host, there was little insect activity evident - but that's the nature of 'no-see-ums'. There were plenty of small mammals keen to share visitors’ food – including grey squirrels to golden-manteled ground squirrels and marmots.

And why the lag in international media coverage until the end of August? The regional California press appear to have begun to cover the hantavirus story around 16^th August. The BBC and other UK media began reporting the news from 28^th August, in part perhaps because US public health authorities had begun to alert Yosemite visitors potentially at risk, typically those who had used tents and tent-cabins into which culprit rodents may have entered.

What is hantavirus? It is one of a family of viruses. Hantavirus infection can affect the skin, lungs, kidneys and other organs. Since the first recognized major outbreak, affecting several thousand US soldiers in the 1950s during the Korean War in the Hanta River region of South Korea, the virus has been detected in many parts of the world, from elsewhere in SE Asia to Scandinavia, mainland Europe and the USA. The type of small rodent carrier varies with geography. Clinical illness appears be rare, with however potentially severe illness in those who are affected, and a high mortality rate, treatment based on supportive measures.

Syndromes caused by hantaviruses differ across geographical regions. Typically old world hantaviruses affect predominantly the skin and kidneys, causing a ‘haemorrhagic renal syndrome’. New World viruses typified by the ‘Sin Nombre Virus’ first described in 1993 usually cause a serious pulmonary syndrome, with around 1-6 weeks incubation period.

Tuberculosis, Bel Ami and the Belle Epoque

Guy de Maupassant

@HealthMed Maupassant's 1885 book Bel Ami concerns the rise to wealth and influence of ex-soldier Georges Duroy, son of a poor rural family. Themes which still have a topical international resonance include the power of the press, foreign wars, corruption in business and government, and stock market insider trading. The anti-hero's success is largely due to the power of the wives of the rich, through their husbands, or direct involvement in political intrigue. A major subplot in Bel Ami is the impact of tuberculosis - estimated to cause the death of between 1 in 4, and 1 in 7 of the population in the mid 19th Century. In Bel Ami, Forestier, a wealthy publisher, develops rapid serious lung involvement, coughing blood, becoming breathless, and fevered. His early death provides a key opportunity for Duroy to enter formally into society.

Belle Epoque France was the outcome of cultural and economic flourishing during the latter part of 19th Century. An obvious question is what people at that time thought about tuberculosis. They knew that is was a serious and often deadly disease: Forestier's rapid death is anticipated as a matter of fact by Clothilde, a faithful companion of Duroy. An important academic view was that the 'soil'' - individual susceptibility - played a major role in the likelihood of developing consumption. There are several apparent similarities between those perceptions and public reaction to the epidemic of HIV-AIDS which emerged in the early 1980s. Tuberculosis was known as consumption because of its wasting effect. The term in translation dates back at least to Hippocrates in 460BCE: the Ancient Greeks used the term phthisis (wasting away) to describe the commonest disease of their time.  This was echoed by the description 'slim disease' for a wasting disorder which emerged in rural Uganda in the early 1980s, strongly associated with infection with the HTLV-III, and thus recognized to be a feature of HIV-AIDS. A major cause of weight loss in HIV-AIDS is associated opportunistic infections such as tuberculosis - a clear illustration of the importance of the impact of impaired host defence on development of a disease.

 

At the time of publishing Bel Ami, Maupassant was ill with syphilis. Not a socially acceptable disease to reflect in a literary work - although ample opportunity for this to be acquired by Maupassant's  anti-hero Duroy and passed on to his high society conquests. The concept of the risk of progressing from a 'night with Venus to a lifetime with Mercury' emerged shortly after the 1494 siege of Naples. In an epic poem of 1530, the Veronese doctor poet Girolamo Fracastoro refers to use of mercury as a possible cure for the disease. And its late effects were well known to Shakespeare, with examples in his play 'Timon of Athens'. One of Fracastoro's many contributions to science and medicine was the idea that certain diseases are spread by particles. In the 1600s, early inventors of microscopy went on to confirm the existence of minute particles. Antoni van Leewenhoek was the first to report single-cell micro-organisms, in 1676 correspondence to the Royal Society, which, after initial scepticism, then confirming his findings, made him a member in 1680. 

A dramatic change in medical thinking and knowledge about tuberculosis occurred in the early 1880s. In 1881, French doctor Louis Landouzy gave a series of influentual lectures on causes of consumption, including speculation that routes of transmission could included infected dust, milk and meat. And in 1882, the Prussian pathologist Robert Koch was the first to describe the causative tubercle bacillus, supported by his formulation in 1884 with Friedrich Loeffler of 4 postulates about the evidence needed to confirm disease causation by microbes. This direct work on the germ theory of disease had been anticipated 350 years before by Frascatoro. Koch's investigations and discoveries in relation to tuberculosis lead to his receipt of the 1905 Nobel Prize in Physiology and Medicine.

The timing of publication in 1885 of Maupassant's novel Bel Ami is therefore of special interest, following 3 years after Koch's discovery. There is no explicit recognition in Bel Ami of the resulting logic for isolating patients with what later became called 'open' tuberculosis - when the TB germs are free to travel from the lungs through the air to nearby contacts. However the move of Forestier to a remote house may have served both to give him a quiet place to convalesce or die, and tacitly to isolate him from at risk friends.

Modern parallels to the public response to tuberculosis in the Belle Epoque range from reactions such as fear, concern and denial for mystery illnesses with no cause known (e.g. pre-HIV 'slim disease'), the response of the public to those affected by HIV-AIDS, before the emergence of effective treatment; and responses to the many types of cancer without known cause, and other  reasons for premature illness and mortality, for example - sudden cardiac death syndromes in young athletes and older adults, despite many advances in diagnosis and treatment.

The Tempest and Prospero's curse - magic, pleurisy, and other thoughts

@HealthMed In response to Caliban's cursing in 'The Tempest', Prospero rewards him with a threatening prophecy: 

'... tonight thou shalt have cramps, 

Side-stitches that shall pen thy breath up ...'

This is a plausible symptomatic description of the intermittent, breath-restricting pain caused by pleurisy [earlier known as pleuritis], a suggestion at least as early as 1886. In contrast, as used by Shakespeare, the word pleurisy denoted a plethora, or excess of blood. This use is thought to have arisen from the idea that the word pleurisy was derived from plus pluris. 
e.g  in Hamlet Act IV, Scene 7:  

"For goodness, growing to a plurisy
 Dies in his own too much."

Pleurisy, local pain and difficulty in breathing, usually arises from inflammation of the pleura - the membranes that lines the lungs and inner walls of the thoracic cage. These inflammatory processes lead to adhesion of the visceral to the parietal pleura.  

Dr Charles Buckmill, writing in 1860, was sceptical of the medical nature of Prospero's curse, seeing it as a blend, half health, half magical in character.

How could Prospero have predicted this would happen to Caliban? Were there poisons at the time [1610-11] that Prospero could have given to Caliban to cause reversible pleurisy? And how did doctors of Shakespeare’s day diagnose pleurisy? The pain of pleurisy is often knife like or cramp-like pain, and worse on inspiration. Pleuritic pain is typically altered by posture, eased in some positions, made worse in others.

These symptoms we now recognize as pleurisy were well-established in Tudor and early Jacobean times; and post-mortem examination was then in European medical centres a route to understanding (or misunderstanding) the nature of disease in retrospect.  The Hippocratic writers were already diagnosing pleuritis from a cluster of symptoms: pain in the side, fever, shivering, rapid breathing, difficulty in breathing when lying flat [orthopnoea] and cough productive of pomegranate-peel coloured or blood-stained sputum. From 300BC, discussion moved to the pathology of pleurisy, with a distinction between disease in the lung (e.g. Herophilus: modern pneumonia) and pleuritis as a disease of the membrane that lines the inner part of the ribs [membrana hypezocota] and resulting in increased pain on lying on the unaffected side [because lung movements than are greater at the site of pleural inflammation], or in some greater when lying on the affected part. 

Pleurisy results in abnormal lung sounds, which, if loud, would have been audible by a physician placing an ear against the chest [auscultation]. This medical diagnostic method is thought to have been used by Ancient Egyptian physicans. However the key early method of diagnosing pleurisy was ‘hardening of the pulse’.

On listening with a stethoscope, a pleural friction rub is heard. Laennec, the inventor in 1816 of the stethoscope, called this friction sound ‘frottement ascendant et descendant’ and ascribed it to emphysematous change in the lungs. Descriptions of the rub include - a scratchy sound similar to that of a door opening on a rusty hinge; or similar to the sound or two pieces of sandpaper rubbed together.  Laennec also used described ‘aegophony’ in pleurisy - a sound like the bleating cry of a goat. Laennec considered that pleurisy was typically associated with modest accumulation of fluid in the pleural cavity (pleural effusion). However with too much pleural fluid, lung sounds disappear, including pleural rubs.

Recognition of pleural effusion goes back to early Babylonian medicine.  Small lead tubes discovered in ancient Babylonian sites are considered to have been trochars – implements inserted through the chest wall to drain pleural fluid. With the benefit of modern imaging, it is now easy to be clear in life that both ‘wet’ and ‘dry’ forms of pleurisy may develop.

Contributors to the germ theory of disease range from Varro in 36BC, to microscope inventor Van Leeuwenhoek’s reports in the 17^th Century, and Semmelweiss and Pasteur in the 19^th Century. Modern medicine recognizes pleurisy, pleuritic pain and its other symptoms as part of a syndrome. Investigations aim to identify the cause of the pleurisy, which might include viral or bacterial infection, pulmonary embolism, immune-mediated disease, kidney failure and tumours. In addition pneumothorax may present wth pleuritic pain. Of note as early as the early 17^th Century, the Paduan Vincent Baronius recognized that patients with pneumonia can also develop pleurisy [pleuripneumony], a concept more widely disseminated by Morgagni a century later.

Back to Prospero’s curse. If not just author’s invention, here are some possible recurrent disorders symptoms of which Prospero could be predicting.

- Pleurisy is typical worse at night, when during attempts at sleep the sufferer may turn to adopt a posture likely to make pleurisy worse and thus awake in pain and breathless.

- Tuberculosis may not be fatal but may leave a patient with pleurisy.

- Malaria was endemic in Shakespeare’s day, including in Mediterranean islands such as Sicily. Attacks of malaria are known sometimes to present with cramping chest pains – and the anaemia of malaria could have made Caliban breathless, especially if were already anaemic. For example his inherited deformed appearance could have had a physical rather than imaginary basis. Thalassaemia – common in the Eastern Mediterranean setting of ‘The Tempest’ - may cause of chronic severe anaemia and is associated with facial deformity.  

- And familial Mediterranean fever (FMF), a genetic disorder common in the Mediterranean,  is a recurrent painful disorder of membranes, including the pleura. And FMF induced joint disease could contribute to a deformed appearance.

Prospero may thus simply have been reminding Caliban of previous or likely medical afflictions. Clearly the scientific details are modern, however these conditions were endemic at the time and present in the right geographical setting for the play.

More on history of pleurisy, stethoscopes and older treatments:

1. Hippocrates. Index of symptoms and diseases. vi. 33. Loeb edition. Translated by P. Potter. London, 1988. 

2. Shakespeare's doctor son-in-law John Hall describes use of scabious as a herbal remedy for ‘pains and stitches in the side’.

3. Laennec, R. T. H. (1819) De l’Auscultation Médiate ou Traité du Diagnostic des Maladies des Poumons et du Coeur. Paris: Brosson & Chaudé.

4. The cyclopaedia of practical medicine: comprising treatises on the nature and treatment of diseases ... Volume 1 Edited by Sir John Forbes, Alexander Tweedie, John Conolly. Publishers Whitaker et al, Paternoster Row, London 1833.

5. The medical knowledge of Shakespeare by Sir John Charles Buckmill MD, Longman, 1860.

6. TCM. Notes from a physician's notebook.  The Cincinnati Lancet. p75, January 16th, 1886.

7. Wilson, A. (2000) On the history of disease concepts: the case of pleurisy, History of Science, Volume 38 (3), 271 – 319. 
 

© DRJ Singer

Advances in treating acute lung syndromes

@HealthMed Although only described as recently as 1967, a range of important contributory factors have been defined for acute respiratory distress syndrome (ARDS), which is now recognized to be at the severe end of a spectrum of acute lung injury, which imposes high risk for patients and which confers a major burden on health services. Outcome of treating the syndrome has been much improved by developments in devices to treat lung and other organ failure, supported by advances in expertise in intensive care. However, other than treatments for underlying causes, there is still important unmet need with regard to effective specific pharmacological treatments.

A timely review of ARDS by Dushianthan and colleagues is the Editor’s choice article in the September issue of the Postgraduate Medical Journal.  These experts from Southampton provide an update on knowledge of risk factors, including genetic biomarkers, for development of ARDS and other acute lung injury variants, and an up-to-date commentary on general and specific treatment options.

The authors note that ‘sepsis, pneumonia, and trauma with multiple transfusions’ account for most episodes. They highlight the importance for recovery of ‘general supportive measures such as appropriate antimicrobial therapy, early enteral nutrition, prophylaxis against venous thrombo-embolism and gastrointestinal ulceration’.

They discuss encouraging experimental evidence from trials of corticosteroids, nitric oxide, prostacyclins, exogenous surfactants, ketoconazole and antioxidants, however note that these findings have not as yet being translated into benefits for patients. They note as further treatment targets of interest, new approaches to modulating inflammation, and use of mesenchymal stem cells.

See the free full article for further details.