The antibiotic course has had its dayBMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3418 (Published 26 July 2017) Cite this as: BMJ 2017;358:j3418
All rapid responses
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.
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.
Competing interests: No competing interests
When I read this study which urges doctors to stop telling their patients to finish an entire course of antibiotics, the first thing I imagined was the impact this message would have on the consumer behavior of Tanzanians who are already grappling with antibiotic resistance. The paper states, “patients should be encouraged to continue taking medication only until they feel better, to avoid the overuse of drugs.” and “Doctors must stop telling patients to finish an entire course of antibiotics because it is driving antimicrobial resistance.”
As a clinical pharmacist coming from a developing nation like Tanzania, where a layman lacks basic health knowledge – this study is very alarming. The impact such a message would have to the public would be detrimental. Experience has shown that whenever studies on such crucial health issues are published in renowned journals, the media here tends to hype the message—and quite often, the public may be left in confusion—more so, if the study is controversial.
My worry is that if this message makes big news here at home, it would cause poor medication adherence to not only antibiotics but other medications as well. Often times in Tanzania, antibiotics can be bought over the counter and many patients self-medicate. As a clinical pharmacist who strives hard to educate patients to complete their course of medications and advise doctors to not prescribe antibiotics irrationally, I find the recent study lacking evidence and needing more research before it can be incorporated into policy.
It is a known fact that poor adherence to antibiotics does lead to bacterial resistance. While I agree that antibiotics are misused, a global or national initiative against antibiotic misuse has been absent especially in the African continent. Currently in Tanzania, Ceftriaxone is widely misused and losing its effectiveness day by day.
The recent study would make healthcare practitioners prescribe the medicine more often for a shorter duration adding to the burden of resistance. This would also cause a firestorm in the media, causing patients to demand short courses from health practitioners, making matters worse. Chloroquine, an antimalarial that was used to treat malaria in Tanzania is now ineffective.
One of the main concerns with irrational drug use is poor adherence and not completing the recommended dose. I believe the focus on curbing antimicrobial resistance should be to have a well-executed national and international plan which involves patient education, surveillance, new research as well as strict laws that stop livestock keepers using antibiotics as animal feed.
The scenario in England is quite different from Tanzania and Africa in general, a message such as the one published in the recent antibiotic study in the BMJ could cripple the health system in Africa as it is. In developed nations, patients can only get antibiotics through a prescription and often times after a culture test is conducted. In Africa, antibiotics can be bought from not only pharmacies but also basic medical stores without a prescription. While the Tanzanian government has tried to curb the problem by making culture sensitivity a compulsory for prescribing some common antibiotics in the National Health Insurance Fund, this is far from the solution. The first step would be to strictly enforce and stop over the counter sale of antibiotics followed by the creation of a national antibiotic policy and guidelines.
It is well-known that antibiotic resistance is a future plague and as Dr. Margaret Chan, the then Director General of the WHO put it, “Resistance to antibiotics could bring an end to modern medicine as we know it.” However, I do believe it is highly inappropriate at this time, to state that patients should be encouraged to continue taking medications only until they feel better. More research to prove this is needed before changes in policy can take place.
Competing interests: No competing interests
This is a well-written editorial with a valid message . 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)  and those receiving intensive chemotherapy,  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 . 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 .
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.
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.
Competing interests: No competing interests
The article by Llewellyn et al (1) discussed an important concept that individualizing the duration of antibiotic therapy may be beneficial in terms of preventing antibiotic resistance. One of the recommendations in the article is to advise patients to stop antibiotics when they feel better. Paradoxically, these self-directed, shorter courses of antibiotics may increase inappropriate antibiotic use because patients will have leftover antibiotics at home.
In our survey of patients in 19 European countries, patient use of antibiotics without a prescription occurred in all participating countries (2). Use without a prescription included obtaining and taking antibiotics without a prescription, taking another person’s antibiotics, or taking one’s own stored antibiotics for an indication other than for which the antibiotic was originally prescribed. Our pan-European study also found consistent associations between prescribed use of antibiotics and self-medication from leftover antibiotics (3). Storage of antibiotics from leftover prescribed courses was also common in our survey of socioeconomically and ethnically diverse primary care patients in the United States. Furthermore, 25% of the surveyed US patients reported that they would use antibiotics without consulting a health care provider (4).
These unsafe practices appear to be associated with antibiotic resistance, as antibiotic use without a prescription has been repeatedly found in countries that report high levels of antibiotic resistance. Use of antibiotics from previous prescribed courses may lead to higher rates of short and frequent antibiotic use, particularly for viral infections, and may foster antibiotic resistance. Other important safety issues related to patient-driven use of leftover antibiotics include adverse drug reactions, drug interactions, masking of underlying infectious processes, superinfection, and disruption of the microbiome.
1. Llewelyn MJ, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ. 2017;358:j3418.
2. Grigoryan L, Haaijer-Ruskamp FM, Burgerhof JG, et al. Self-medication with antimicrobial drugs in Europe. Emerg Infect Dis. 2006;12(3):452-459.
3. Grigoryan L, Burgerhof JG, Haaijer-Ruskamp FM, et al. Is self-medication with antibiotics in Europe driven by prescribed use? J Antimicrob Chemother. 2007;59(1):152-156.
4. Zoorob R, Grigoryan L, Nash S, Trautner BW. Nonprescription Antimicrobial Use in a Primary Care Population in the United States. Antimicrob Agents Chemother. 2016;60(9):5527-5532.
Competing interests: L Grigoryan reports a grant from Zambon Pharmaceuticals.
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!
Competing interests: No competing interests
What I learnt at university about bacterial infections was quite simple, because I thought I understood the key-message: The host versus microbe interaction decided whether or not to prescribe antibiotics, including for how many days.
What I learnt from this BMJ Analysis article is only that the BMJ is a platform which causes a lot of discussion amongst doctors and a lot of confusion amongst patients. The former is welcome, the latter not, especially because the confusion of the public on ‘stopping the antibiotic course when feeling better’ will augment the global threat of antibiotic resistance. Two reasons:
a) The doctor versus patient interaction. Doctors, claiming to be experts, tell other doctors to change their policy. Patients in the Netherlands, readers of highly rated daily newspapers such as De Volkskrant and Trouw, read the message of stopping any antibiotic course when feeling better. These readers are not aware of the fact that the authors advocate patient centred decision making, which is a dangerous concept when the issue is still under medical debate. My patients want information on diagnosis and prognosis of an expert, being their doctor. Only on this condition, shared decision making may follow. Now however, my patients might think that the antibiotic course I prescribed is not that important, and may preserve half of the course for the next time they will have similar complaints. Thus, courses shortened by patients will result in more frequent use of antibiotics and in more antibiotic resistance. In this way, the public’s incomplete understanding of antibiotic resistance (1) will be further undermined.
b) The host versus microbe interaction. Table 1 suggests a balanced overview of trials assessing the effects of duration of treatment. For my specialty, streptococcal pharyngitis, the cited Cochrane review does not show any effect of duration, because the trials compare 10 days penicillin with 3-6 days of other antibiotics: The classic comparison between apples and pears. Our research-group compared 7 days penicillin with 3 days and with placebo (2), (3). We found for penicillin given for 3 days a tendency to prolong the period of sore throat in the first week and to increase the recurrence rate in the following 6 months. We hypothesized that the short duration of penicillin treatment only suppressed the pathogenic streptococci without eradicating them. Thus, another interaction between host and microbe than antibiotic resistance was possibly harmful to the patients receiving a too-short course.
I was happy to read in today’s newspaper a comment of a Dutch expert, professor of infectious dieases, on the headlines ‘Completing antibiotic course? Nonsense’. He advised the public to ask the GP for advice (4). My conclusion: Patient centred decision making is an illusion when the medical debate is still ongoing.
1) McNulty CA, Nichols T, French DP, Joshi P, Butler CC. Expectations for consultations and antibiotics for respiratory tract infection in primary care: the RTI clinical iceberg. The British Journal of General Practice. 2013;63(612):e429-e436. doi:10.3399/bjgp13X669149.
2) Zwart S, Sachs APE, Ruijs GJHM, Gubbels JW, Hoes AW, de Melker RA. Penicillin for acute sore throat: randomised double blind trial of seven days versus three days treatment or placebo in adults. BMJ : British Medical Journal. 2000;320(7228):150-154.
3) Zwart S, Rovers MM, de Melker RA, Hoes AW. Penicillin for acute sore throat in children: randomised, double blind trial. BMJ : British Medical Journal. 2003;327(7427):1324.
4) Marc Bonten. Maak dat kuurtje toch maar af. Dagblad Trouw, August 8th 2017.
Competing interests: No competing interests
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. 
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,
1 Coemgenus. Should you complete your course of antibiotics? Journal Of the Royal College of Physicians of London (JCPRL) 1999; 33 (6): 594
Competing interests: No competing interests
In this “Analysis”, Llewelyn et al argue that clinicians put patients at unnecessary risk when prescribing standard duration of antibiotics, advising them to defect from international “complete the course” recommendations.1
I would, however, argue that these authors’ rational is based on vague assumptions and that robust evidence on the causality of the spread of antibacterial drug resistance in the community is needed before making such claim.
First, the authors state that antibiotic use replaces commensal flora of the gut or skin with “resistant species and strains ready to cause infection in the future” 1 However, their argument is based on a study that only observed selection of non-ESKAPE resistant bacteria such as coagulase-negative staphylococci and oral nongroupable streptococci.2 In addition, ESKAPE organisms including Pseudomonas spp or Staphylococcus aureus were not isolated, outright refuting the authors main claim.1
Second, although most antibiotics (85%) prescribed are issued in primary care, for many of these drugs (e.g. amoxicillin used for respiratory tract or ear infections) no safe narrow-spectrum alternatives exist.3 Also, drug resistance to broad-spectrum antibiotics (e.g. piperacillin/tazobactam or carbapenems) amongst ESKAPE organisms has largely emerged from over-prescribing in hospital settings rather than primary care where these drugs are not available.4
Third, the authors also ignore other important forms of selection pressure on bacteria such as farming and the food industry, easy over-the-counter access to antibiotics overseas, and patients borrowing drugs from friends or family for minor illnesses.
Fourth, the authors also claim that drug resistant bacteria are “transmitted between asymptomatic carriers rather than people with disease”. Again, the paper cited to back up their argument describes a within-hospital outbreak of carbapenem-resistant Enterobacter spp with little or no evidence for import from or spread to the local community.5 Therefore, claiming a simple link between fixed-course antibiotic regimens and the spread of drug resistance in the population, combined with advice that patients shorten the duration of their treatment, is speculative at its best and dangerous at its worst. Therefore, before making such a claim the authors should provide rigorous analysis of epidemiologic and phylogenetic data (as has been done for HIV, malaria, and TB) to back up their argument.6
As a primary care clinician, I would be very happy to prescribe shorter treatments if clear evidence for doing so was available from systematic reviews or randomised controlled trials. Until proven otherwise, however, I will not change my prescribing behaviour and continue to provide the “complete the course” standard of care to my patients for the sake of their safety and for medico-legal reasons.
1. Llewelyn MJ, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. Bmj 2017;358:j3418. doi: 10.1136/bmj.j3418 [published Online First: 2017/07/28]
2. Cremieux AC, Muller-Serieys C, Panhard X, et al. Emergence of resistance in normal human aerobic commensal flora during telithromycin and amoxicillin-clavulanic acid treatments. Antimicrobial agents and chemotherapy 2003;47(6):2030-5. [published Online First: 2003/05/23]
3. Schneider-Lindner V, Quach C, Hanley JA, et al. Secular trends of antibacterial prescribing in UK paediatric primary care. The Journal of antimicrobial chemotherapy 2011;66(2):424-33. doi: 10.1093/jac/dkq452 [published Online First: 2010/12/22]
4. Lob SH, Hackel MA, Kazmierczak KM, et al. In Vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens Isolated by Clinical Laboratories in the United States in 2015 (Results from the SMART Global Surveillance Program). Antimicrobial agents and chemotherapy 2017;61(6) doi: 10.1128/aac.02209-16 [published Online First: 2017/03/23]
5. Sheppard AE, Stoesser N, Wilson DJ, et al. Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene blaKPC. Antimicrobial agents and chemotherapy 2016;60(6):3767-78. doi: 10.1128/aac.00464-16 [published Online First: 2016/04/14]
6. Wilson BA, Garud NR, Feder AF, et al. The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens. Molecular ecology 2016;25(1):42-66. doi: 10.1111/mec.13474 [published Online First: 2015/11/19]
Competing interests: No competing interests
Duration of antibiotic therapy: Fixed duration versus personalization/Individualization of antibiotic therapy duration: which one to be preferred?
We too feel that fixed duration antibiotic therapy may expose patients to under-treatment or overtreatment by an antibiotic. Underexposure is associated with therapeutic failure and consequent adverse outcomes. Longer exposure to antibiotic is associated with selective growth of resistant populations and emergence of a drug resistant colony. In our view, it is better to go for personalized duration of antibiotic therapy rather than a fixed duration antibiotic course. Personalized duration can balance both under and over treatment as the duration of treatment is decided on the basis of patient disease activity parameters. (1) Personalization balances disease progression and its complications and risk associated with antibiotic use i.e. resistance to antibiotics and adverse drug reactions. (2)
There are many personalization strategies like use of clinical markers and biomarkers for deciding duration of antibiotic therapy. The Infectious Disease Society of America (IDSA) recommends discontinuation of antibiotic therapy in patients suffering from community acquired pneumonia after 5 days if he fulfils clinical stability criteria. (2, 3). In addition to clinical stability criteria, biomarkers are being used increasingly to decide the requirement, monitoring and the duration of treatment. Several algorithms are in use based on procalcitonin (PCT), C reactive protein (CRP) and risk assessment tools based on level of pro-adrenomedullin (ProADM). PCT has been used as a decision maker tool in CAP, sepsis, urinary tract infections, postoperative infections, meningitis etc. (4, 5, 6) In severe infections, use of PCT kinetics as a decision maker tool resulted in shorter duration of antibiotic therapy with early cessation. These biomarker based treatment strategies did not result in increase in mortality, recurrence of infection or failure of treatment or increase in adverse effect. (6) Personalization also added economic advantage. In “SAPS”study, use of PCT based protocol resulted in mean reduction in antibiotic cost by €34 per patient. (7)
ProADM is used along with clinical scoring systems for risk stratification. (3, 4) Many other promising biomarkers are evaluated in different clinical scenarios e.g. sTREM-1 (pneumonia, meningitis and sepsis), suPAR/CD87 (sepsis), ProADM (pneumonia), Presepsin (sepsis), PTX3 (sepsis) etc. (9, 10)
Regarding future prospectives, we need to focus on more personalized strategies like use of precision peptides for killing bacteria and at the same time preserving microbiota. Use of system pharmacology approach and machine learning techniques can help us further individualizing the approach. CRISPR-Cas has been used to target specific antibiotic resistance genes to remove drug-resistant organisms selectively in pure cultures and in complex microbial consortia. (11) So, to conclude, we think that use of personalized antibiotic therapy is the future of antibiotic therapy. It is the need of the hour, to develop new biomarkers and gather evidence on the same from adequately powered clinical studies.
1. Llewelyn MJ, Fitzpatrick JM, Darwin E, et al. The antibiotic course has had its day. BMJ 2017;358:j3418.
2. Lee JS, Giesler DL, Fine MJ. Duration of Antibiotic Therapy for Community-Acquired Pneumonia in the Era of Personalized Medicine. JAMA 2016;316(23):2544-2545.
3. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44 Suppl 2:S27-72.
4. Schuetz P, Litke A, Albrich WC, et al. Blood biomarkers for personalized treatment and patient management decisions in community-acquired pneumonia. Curr Opin Infect Dis. 2013;26 (2):159-67.
5. Póvoa P, Salluh JI. Biomarker-guided antibiotic therapy in adult critically ill patients: a critical review. Ann Intensive Care. 2012; 2 (1):32.
6. Sager R, Kutz A, Mueller B, Schuetz P. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med. 2017;15(1):15.
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Competing interests: No competing interests
Before reading the article I suspected it could be non-sense. After reading it I am pleased with an excellent thoughtful article. There is no new information in this work, no new experiments, test, essays; what is different in this article is the rational construction it makes of (widely?) known facts. The authors change the epistemic frame (1-2). They stop thinking in terms of the illness and the particular bacteria producing it in the particular individual and rather think in terms of the antibiotic altering the ecosystem of the individual (including, but not only, the intestinal flora) and the well being of the human species. Changing the epistemic frame makes possible new questions and new research directions, and this is precisely what the article does. An excellent article, no doubt about it!
(1) ,J Piaget and R García. Psychogenesis and the History of Science, Columbia University Press (New York)}, 1989,
(2) H G Solari, Epistemic considerations on research about Flavivirus induced fevers. Journal of Fever 1 (1), March 2017. http://www.jscimedcentral.com/Fever/fever-1-1002.pdf
Competing interests: No competing interests