Monday, 5 May 2008

Antibiotics and Evidence versus Eminence Based Medicine

Dear Bloggers

I hope that you are having an enjoyable Golden Week. The weather is not particularly golden and more like 'lead'- grey with it being overcast :-(

Today I would like to focus on the duration of antibiotic usage for treatment of pneumonia. The 'recommended' duration of intravenous antibiotic use is widely accepted to be a week to 10 days or sometimes longer. From one colleague I had heard that intravenous antibiotics are routinely given for infections resulting in positive blood cultures for a standard of two weeks even if the patient has recovered, despite the underlying cause. In many of the traditional textbooks and handbooks covering the use of antibiotics, there is the standard use of 7-10 days of antibiotic use in pneumonia. However, where is the evidence for this widely accepted dogma??

A team from the Netherlands attempted to investigate whether an abbreviated three-day course of intravenous amoxicillin was inferior to an 8-day course of amoxicillin consisting of 3 days of initial intravenous therapy followed by 5 days of orally administered amoxicillin for use in mild to moderate-severe community acquired pneumonia.

Patients were included in the study if they had symptoms and signs of pneumonia plus radiological evidence of the diagnosis. They all received high-dose intravenous amoxicillin for 3-days after which, if there was seen to be improvement e.g. feeling better, reduced sputum, fever reduction etc, the patients either received placebo or high dose oral antibiotics for a further 5 days.

The results were astonishing in that a 3-day course of intravenous amoxicillin was observed not to be inferior to an 8-day course of amoxicillin for the treatment of mild to moderate-severe community acquired pneumonia.

As 60-80% of admitted patients have mild to moderate-severe pneumonia [pneumonia severity score <110], it is therefore conceivable that most hospitalized patients with CAP could be treated with high dose intravenous amoxicillin for just 3 days.

The majority of bacterial isolates were the usual culprits of Streptococcus pneumoniae followed by Haemophilus influenza.

The study had less than 200 patients and the 3-day-treatment-placebo group had worse symptoms than the 8-day-treatment group on admission but the overall cure outcome in the 3-day group was statistically non-inferior to the 8-day group.

It seems logical that antibiotics when given either orally or intravenously for specific infections e.g. CAP, uncomplicated UTI, should be done so at high-dose and for a short period of time if there are no complicating factors. The idea behind this is that the Minimum Inhibitory Concentration can be achieved as the serum level is high and with a short duration of administration reduces the exposure of bacteria to prolonged periods of antibiotics which is known to promote antibiotic resistance.

Moreover, the longer that antibiotics are continued, the more side-effects that one gets such as drug-associated fevers, drug induced rashes and antibiotic associated colitis e.g. Clostridium difficile infection.

Short course antibiotics lead to reduced expense on antibiotics, reduced hospital stay and reduced exposure to hospital acquired infections.

Patients should not be kept in hospital just because of the widely accepted dogma that 10-days of antibiotics have to be administered. There needs to be a re-evaluation of the current thinking so that evidence is used when treating patients rather than eminence based opinion.

One thing I have noticed commonly is the use of low dose prolonged courses of antibiotics. I cannot see the use for such prolonged courses especially when side effects are increasingly common. In the BMJ study, the three-day course was associated with no observed side-effects as opposed to the 8-day course which was associated with side-effects. Moreover, if low-dose antibiotics are used, then the MIC cannot always be effectively achieved and would also promote resistance and failure to achieve a clinical and/or bacteriological cure.

To rely on rigidly fixed doses for use of antibiotics is not logical because patients have all different weights, volumes of distribution depending on body fat, and they may have underlying renal or liver disease which ultimately affects the final dose that can be used. Just consider for one moment the use of weight per kilogram per day of antibiotic administration akin to childrens dosing.

The following examples may surprise you of just how much antibiotic is recommended. Obviously, doses and duration of antibiotics depends on the underlying infection, the patient’s immunity, renal and hepatic disease plus local bacteriological resistance factors.

For example, the maximum allowed oral dose of amoxicillin in Japan is 250mg three times daily. However, if one uses the paediatric dosing according to world standards e.g. 40mg/kg/day and if for example an adult patient is 40kg, the total daily dose required is 1600mg. Divided into thrice daily dosing, this equates to over 500mg per dose [533mg to be precise]. Hence, the dose allowed to be prescribed is half of what is recommended to be given to adult patients according to world standards.

As a consequence, with this single example, it may to some extent explain why some community acquired pneumonias and urinary tract infections are only partially treated in the community thereby requiring hospital admission for higher dose intravenous antibiotic administration.

A further example is the use of clarithromycin-- maximum daily dose in Japan is 200mg twice daily. However, if one uses the pediatric world dosing standard which is 7.5mg/kg/day every 12 hours, in a 40kg patient, the dose would be 300mg per dose. Obviously, for larger patients the dose would be higher. In fact, the recommended world dose for adults is 500mg twice daily.

One other final example is the aversion to use Benzylpenicillin (Penicillin G) in pneumococcal pneumonia for fear of not covering the Penicillin Resistant Streptococcus Pneumoniae [PRSP]. This aversion is unfounded because pneumococcal pneumonia can be effectively treated with this well established antibiotic even for PRSP so long as it is used at high-dose e.g. 2 mega units, six times daily [total of 12,000,000 units daily].

A recent example from another hospital was a female patient with a typical uncomplicated community acquired pneumococcal pneumonia who was treated with the high-dose Penicillin G regimen and who had antibiotics stopped after just 4 days because of complete resolution of symptoms. She was discharged on day 5 with early outpatient follow-up. Penicillin G does work ! :-)

Finally, in the Netherlands 3-day pneumonia treatment study mentioned above, the intravenous dose is not mentioned but the 5-day oral course was 750mg three times daily-- hence, high dose!

This study demonstrates that for specific case definitions e.g. mild to moderate-severe community acquired pneumonia, the use of a three day course of intravenous amoxicillin is not inferior to three days of intravenous therapy followed by five days of high dose oral amoxicillin [total of eight days treatment].

If you are interested in reading this fascinating research it can be read for free on

The reference is:

el Moussaoui et al. The effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community acquired pneumonia: randomised, double blind study. BMJ. Vol 333, 30 Sep 2006.

Please Consider....

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