The antibiotic course has had its day

Martin Llewelyn et al published in July 26th 2017 in the British Medical Journal an article entitled "The antibiotic course has had its day" (1). The authors refer to the relationship between exposure to and the development of resistance to antibiotics, at both the individual and population levels, and promote the reduction of unnecessary use of antibiotics in line with the objectives of the World Health Organization (2). The article mentions the replacement of the commensal flora of subjects receiving antibiotics for resistant strains, the greater risk of developing resistance with prolonged courses of antibiotics and highlights the scarce evidence that support the current treatment duration recommendations. Finally, the authors suggest replacing the term "complete the course" by taking antibiotics "exactly as prescribed".

We share the concept expressed by the authors that a course of antibiotics with pre-established duration and similar for all patients ignores the fact that different subjects respond differently to treatment. However, for most outpatient infections there are no clear predictors of early antibiotic response that allow for the "individualization" of length of therapy in each patient. The authors suggest that "in many situations, stopping antibiotics sooner is a safe and effective way to reduce antibiotic overuse" and suggest that a simple and appropriate alternative would be to advise the patient “to stop when you feel better". In ambulatory practice, where the highest consumption of antibiotics is generated, patients with mild to moderate severity of infection are not usually reassessed in the course of the infectious disease, and for this reason the physician establishes the duration of antibiotic treatment in the first visit. We do not believe that the duration of treatment should be delegated to the patient's discretion, but should be prescribed taking into account the shortest possible duration based on existing evidence.

Although evidence supporting the duration of antibiotic treatment is scarce, in recent years a considerable number of publications have shown that short courses of antibiotics are sufficient to obtain clinical and microbiological cure in most outpatient infections (3- 6).

The Infectious Diseases Society of Argentina has developed recommendations for the treatment of frequent infections in the community to avoid the unnecessary prescriptions of antibiotics, to use those of reduced spectrum and to prescribe short courses of antibiotics (7-11) and thus considerably reduce the burden of antibiotics to which the community is exposed.

Prolonged antibiotic courses should have their days counted, and be replaced by short courses.

1. Llewelyn MJ, Fitzpatrick JM, Darwin E, SarahTonkin-Crine, Gorton C, Paul J, Peto TEA, Yardley L, Hopkins S, Walker AS. The antibiotic course has had its day.
BMJ. 2017 Jul 26;358:j3418. doi: 10.1136/bmj.j3418.

2. World Health Organization. Global action plan on antimicrobial resistance 2015. http://www.wpro.who.int/entity/drug_resistance/resources/global_action_p...

3. Falagas ME, Karageorgopoulos DE, Grammatikos AP, Matthaiou DK. Effectiveness and safety of short vs. long duration of antibiotic therapy for acute bacterial sinusitis: a meta-analysis of randomized trials. Br J Clin Pharmacol 2009; 67: 161-71.

4. Dimopoulos G, Matthaiou DK, Karageorgopoulos DE, Grammatikos AP, Athanassa Z, Falagas ME. Short- versus long-course antibacterial therapy for community-acquired pneumonia : a meta-analysis. Drugs 2008; 68: 1841-54

5. Uranga A, España PP, Bilbao A, et al. Duration of antibiotic treatment in community-acquired pneumonia: a multicenter randomized clinical trial. JAMA Intern Med 2016;358:1257-65. doi:10.1001/jamainternmed.2016.3633. pmid:27455166.

6. Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;358:1669-74. doi:10.1001/archinte.164.15.1669 pmid:15302637.

7. http://www.sadi.org.ar/recomendaciones-y-consensos/item/26-consenso-inte...

8. http://www.sadi.org.ar/recomendaciones-y-consensos/item/44-recomendacion...

9. Lopardo G, Basombrío A, Clara L, Desse J, De Vedia L, Di Libero E, Gañete M, López Furst MJ, Mykietiuk A, Nemirovsky C, Osuna C, Pensotti C, Scapellato P. Guidelines for management of community-acquired pneumonia in adults. Medicina (B Aires). 2015;75(4):245-57. Spanish.

10. Lopardo G, Pensotti C, Scapellato P, Caberlotto O, Calmaggi A, Clara L, Klein M, Levy Hara G, López Furst MJ, Mykietiuk A, Pryluka D, Rial MJ, Vujacich C, Yahni D. Inter-society consensus for the management of respiratory infections: acute bronchitis and chronic obstructive pulmonary disease. Medicina (B Aires). 2013;73(2):163-73. Spanish.

11. Lopardo G, Calmaggi A, Clara L, Levy Hara G, Mykietiuk A, Pryluka D, Ruvinsky S, Vujacich C, Yahni D, Bogdanowicz E, Klein M, López Furst MJ, Pensotti C, Rial MJ, Scapellato P. Consensus guidelines for the management of upper respiratory tract infections. Medicina (B Aires). 2012;72(6):484-94. Spanish.

Dear Editor

This is a well-written editorial with a valid message [1]. However, we believe that the authors have ignored the experience with selective digestive decontamination (SDD) and the emergence of antimicrobial resistance [2,3]. Critically ill children who have received SDD, such as those treated on the intensive care unit (ICU) [2] and those receiving intensive chemotherapy, [3] rarely develop the emergence of resistant potentially pathogenic micro-organisms (PPMs). They generally clear overgrowth with PPMs from the throat and gut during SDD treatment.

If overgrowth is eradicated successfully, resistance is unlikely to emerge. However, if overgrowth is not eradicated, resistance is more likely to occur.

The intravenous component of SDD, Cefotaxime, is excreted into the throat via saliva in high concentrations and clears Streptococcus pyogenes and Staphylococcus aureus overgrowth. The oral components of SDD, polymyxin E and tobramycin, clear overgrowth of aerobic Gram-negative bacilli (AGNB) from the gut [4]. Oral polyenes, e.g., amphotericin B and nystatin effectively eradicate fungal overgrowth.
The oropharyngeal and intestinal overgrowth of potential pathogens (≥105 PPMs per mL) has recently been shown to promote the emergence of antimicrobial resistance and is associated with increased spontaneous mutations and polyclonality of both sensitive and resistant clones [4].

Intravenous antimicrobials, which are excreted via saliva and intestinal fluids into the gut in sub-lethal concentrations, are more likely to select resistant clones

The editorial presumably mainly refers to patients in general practice, in whom we know of few data on gut PPM overgrowth. This contrasts with extensive studies in the critically ill. General practice patients do not suffer overgrowth as they have peristalsis, which also guarantees drug absorption. Following absorption, oral antibiotics are subsequently excreted via saliva and bile. Absorption is impaired in critically ill patients who require parenteral antibiotics. The non-absorbable antimicrobials of SDD are designed to prevent and clear the overgrowth of PPMs in the alimentary canal during critical illness.

In conclusion, we believe that the development of microbial overgrowth in the gut during antimicrobial therapy, rather than the non-completion of a prescribed antibiotic course, is likely to promote the emergence of antimicrobial resistance.

References
1. Llewellyn MJ, Fitzpatrick JM, Darwin E et al. The antibiotic course has had its day. BMJ 2017; 358: j3418. doi: 10.1136/bmj.j3418
2. Sarginson RE, Taylor N, Reilly N et al. Infection in prolonged pediatric critical illness: A prospective four-year study based on knowledge of the carrier state. Crit Care Med. 2004; 32: 839-847.
3. Paulus SC, van Saene HKF, Hemsworth S et al. A prospective study of septicaemia on a paediatric oncology unit: a three-year experience at The Royal Liverpool Children's Hospital, Alder Hey, UK. Eur J Cancer 2005; 41: 2132-2140.
4. Taylor N. The addition of enteral to parenteral antibiotics may prolong the antibiotic era. MPhil Thesis 2014. University of Liverpool.
5. van Saene HKF, Taylor N, Damjanovic V, Sarginson RE. Microbial gut overgrowth guarantees increased spontaneous mutation leading to polyclonality and antibiotic resistance in the critically ill. Current Drug Targets 2008; 9: 419-421.

Martin Llewelyn and colleagues argue that "with little evidence that failing to complete a prescribed antibiotic course contributes to antibiotic resistance, it’s time for policy makers, educators, and doctors to drop this message." What surprises everyone is that this sober statement followed, tabloid style an attention grabbing, misleading headline, which asserted that "The antibiotic course has had its day".

Maybe the BMJ editorial team chose this title and the authors blindly endorsed the choice. Most of the rapid responses were critical of the tone and content of the article. One of the readers called it an opinion piece.

DR ABDUL GHAFUR, Consultant in Infectious diseases, Apollo Cancer Institute, Chennai, India in his rapid response, has been very blunt in voicing his concern, thus: "It is true that controversial articles create widespread discussion on important issues. Unfortunately, this article has probably done more harm than good to the field of antibiotic stewardship. This article is based on concrete facts, but written in a highly misleading way and interpreted by media and the public in a dangerously erroneous style."

While many news outlets reproduced the telling title of the paper written by 10 senior researchers, very few of them made critical analysis of the issues. The Hindu, which publishes a very popular Science and Technology section is an exception. It bemoaned the fact that the media’s coverage of the article too was unquestioning. It referred to an article in The Guardian, titled “Rule that patients must finish antibiotics course is wrong, study says" with a subtitle “Experts suggest patients should stop taking the drugs when they feel better rather than completing their prescription”. The Hindu article noted that it was shared 25,000 times.

A telling blog titled "Why BMJ’s advice to ‘stop taking antibiotics when you feel better’ should be ignored" by Dr. R. Prasad, the Science Editor, The Hindu, is unambiguous and clear.

He found out how widely the wrong message had spread by reviewing the Altmetric score of the BMJ paper on August 14, 2017

"With an Altmetric score of 3,244, it falls in the top 5% of all research outputs scored by Altmetric. From The BMJ, it is the second highest scoring paper. The number of newspapers that have covered this paper stands at 187; the actual number would be much higher as not all newspapers get counted by Altimetry", Dr. Prasad clarified.

"There have been nearly 3,000 tweets and 92 Face book pages about this paper. It has been shared the most in the UK with a score of 300, closely followed by the U.S. with 271." he added

Considering the unguided and unmonitored influence of social media, impartial observers may wonder whether it is better to conduct such controversial discussions on antibiotics, etc, in seminar halls or scholarly academies to arrive at appropriate guidelines before medical journals publish them!

Dear Sir

The authors are to be congratulated on their courage in publishing this excellent discussion. The piece below was published in Clinical Medicine under the pseudonym 'Coegemus' in 1999. [1]

Two of the most intelligent people I have known, Dr Harold Lambert, whose publication of 1999 is referred to in the article, and the Professor of Bacteriology Richard Lacey of BSE fame both held these views nearly 20 years ago.

In my informal article in which the problem is discussed with a fictitious intelligent layman, I made two points that might help in persuading the medical tradionalists and the general public the logic of the author's case. First that relapse due to too short a period treatment must be with a sensitive organism as was shown when establishing duration of two drug therapy in tuberculosis. Secondly the time scale of bacterial reproduction is such that a much shorter period than conventional courses is almost certain to be adequate.

"There has been much concern about drug resistance in the profession and lay media recently. It so happened that Charles and a distinguished though flamboyant professor of Bacteriology came to dine one night. I broke the rule about not introducing shop.

“Are suitable antibiotics going to run out, or do you think the drug manufacturers will always be ahead of the game?“ I asked.
“Some GPs don’t seem to help” said Charles. “Last week my wife caught an infection from my daughter’s family for whom she baby sits. Kate and her two pre-school children had nasty illnesses starting with colds. My wife got so many aches and pains, that she thought she ought to go to the doctor to make sure it wasn’t something different. He prescribed an antibiotic, telling her she must complete the course”.
“Yes,” said the professor. “In a previously fit lady and with the obvious source, the chance of bacterial infection was virtually nil. Doubtless the doctor explained that she had a virus, but was giving a precautionary antibiotic just in case it was bacterial, and claimed that your wife expected a prescription, which I suspect was not true”.

Charles nodded and I interjected “Once I circularised general practitioners, asking what prior chance of an antibiotic being appropriate justified its prescription. I explained that I expected a lower threshold in general than in hospital practice, where observation was easier. Unfortunately most of them didn’t seem to understand the question” .
“That’s no surprise” Charles said, “although, of course, it is the critical question”.
“Yes” I went on “nevertheless whether appropriately prescribed or not, the course should always be completed”.
“I am not sure” said the professor. “I had been known to say that fortunately most people don’t”.

Seeing my surprise, he asked Charles “Has the layman any further thoughts?”
“First I would like to know what determines whether an organism causes an infection, and the time scale involved”.
“A portal of infection, the organisms virulence, and the host’s defences” said the professor. “In the previously fit individual, the window of opportunity may be very short, and the organism very virulent, for example, in pneumococcal and meningococcal disease”.
“How often do these germs divide?”
“They divide about every twenty minutes, so a single organism becomes a mass several millimetres in diameter within twenty four hours”.
“Seventy generations a day, equivalent to two thousand years for the human race. Don't you think that treatment for a day, or two millennia, might be overkill?”
I acknowledged that a single dose may effectively treat simple urinary tract infection, but countered “But surely, we want to be certain to mop up the remaining organisms”.
“How long do you prescribe for? Five or seven, but not six, days. I suspect, for no better reason than that there are five digits on each hand, and seven days in the week” said Charles answering his own question. “The longer you go on surely the more likely you are to be showing the antibiotic to organisms incidentally on body surfaces, than mopping up accessible organisms not already killed by an antibiotic, to which they are exquisitively sensitive”.

He continued “Recently my son did have pneumococcal pneumonia. He was given injections for 24 hours before switching to a lower dose of oral antibiotic, whose absorption was compromised by actually making him sick. His temperature fell to normal after the first injection. If organisms were lurking in nooks and crannies, and were not killed by several injections, one of which was clearly enough for the majority, wouldn’t you require higher, not lower doses, to eradicate them?”
“But what if treatment is just not long enough?” I asked.
“The germ can’t be resistant if the next dose would kill it”.
“So you suggest to avoid inducing antibiotic resistance in other potential pathogens on body surfaces, we should give high doses until recovery and only worry about relapse if it occurs, probably with the organism still sensitive”.
“That’s right, Coe”.

“You have a point” said the professor. “When the MRC conducted the classical studies progressively shortening the course of treatment for TB, relapse did occur with sensitive organisms. On the other hand they did show the value of an intense initiation phase followed by maintenance therapy continued long after clinical recovery. On second thoughts, this may not be applicable to the acute infections that we are thinking about, as tuberculosis is very different. The host element is large, generation time longer and treatment usually started later. Clinical disease, not a one off event, follows a vicious downward circle, which on being reversed improves host resistance and possibly makes the organisms more rather than less accessible”.
“Don’t you think similar experiments should be done with acute bacterial infections?” Charles asked.
“Yes, but cautiously, relapse might be more dangerous”.
“Who would fund them?” I asked.
“Government” Charles replied.
The professor agreed “Cynicism is unnecessary, drug companies have to count the cost of relicencing even where clinical practice exceeds licence indications. A job for NICE?” "

I hope that the ideas given in the informal format might help in persuading sceptics that the authors are absolutely correct so far as the management of acute primary infections is concerned,

Yours faithfully

CK Connolly

Reference
1 Coemgenus. Should you complete your course of antibiotics? Journal Of the Royal College of Physicians of London (JCPRL) 1999; 33 (6): 594