Antibiotics: the Dosage Debate

30 September 2008 (Last Updated September 30th, 2008 18:30)

Is prevention always better than cure? Peter Wilson of University College London Hospital examines the risks of infection through prophylactic antibiotic use.

Antibiotics: the Dosage Debate

Antibiotic prophylaxis uses many doses of antibiotic as does treatment. Most hospitals have protocols regarding the optimal use of antibiotic prophylaxis but these are observed to varying degrees. Two developments have recently affected the advice that microbiologists give and yet remain controversial. Some clinicians do not accept the advice.

Theoretical, practical and clinical studies now suggest that antibiotic prophylaxis should be given as one or two doses from the start of surgery and not one to three days after. However, some surgeons are still giving prolonged courses in the belief they are more effective.

Similarly in the prevention of endocarditis, new guidelines in the UK and to a lesser extent the US have reversed the last 50 years of practice by recommending no prophylaxis is given to cover the great majority of procedures in patients with valvular defects. Although adequate evidence is lacking either way, giving antibiotics for the benefit of the doubt is no longer endorsed.

Dosage and adverse events

There is an accumulating body of evidence that for many types of surgery a single dose of antibiotic is adequate to prevent surgical infection, provided serum levels remain adequate throughout surgery. Additional doses during surgery lasting more than four hours are reasonable and maintain adequate tissue levels of antibiotics with a short half-life.

Courses longer than 24 hours have no advantage in most cases, although many surgeons continue to use them. However, in some procedures, such as arthroplasty, courses of 24 hours appear to be associated with better outcome than single doses. If antibiotics are given over longer periods the risks of adverse events such as rash, gastrointestinal upset and Clostridium difficile are increased, aside from the unnecessary cost.

Antibiotics do not eliminate all potential invading organisms from an area with endogenous flora. The longer antibiotics are given, the more opportunistic infections can occur and increase the final rate of infection. Dose, duration, rate of administration and timing relative to surgery all affect the effectiveness of prophylaxis. Antibiotics limited to the day of operation are less likely than postoperative antibiotics to encourage the emergence of resistance and superinfection. They should reach the optimum concentration for bacterial killing at the time of maximum contamination and the four hours thereafter.

"There is an accumulating body of evidence that for many types of surgery a single dose of antibiotic is adequate to prevent surgical infection."

In maxillofacial surgery, a systemic analysis of trials concluded antibiotics reduced infection rates three-fold but single-dose, single-day or multiple-day regimens were similarly effective. Organisms entering the wound before treatment were eliminated by antibiotics and resulted in fewer infections. In septorhinoplasty, perioperative antibiotics for 24 hours were as effective as a week-long course of empirical postoperative antibiotics. A postoperative course was less likely to penetrate the site of contamination.

In a randomised double-blind trial in orthognathic surgery patients were given two perioperative doses of amoxicillin, followed by five days of amoxicillin or placebo. There was no appreciable difference in the number of patients requiring antibiotic treatment, although the longer course recipients tended to have less swelling. However, there remained a wide range of infection rates between surgeons in that centre, as well as disagreement over what constituted an appropriate length of prophylactic course.

For acute appendicitis without perforation, a randomised trial compared 92 patients given a single preoperative dose, 94 given three doses and 83 given a five-day course of cefuroxime and metronidazole.

All groups had similar incidence of postoperative infection (6.5%, 6.4% and 3.6% respectively). There was no relationship between length of antibiotic course and hospital stay but Clostridium difficile colitis was significantly more common with the longer course.

A systematic review of randomised trials of antibiotic prophylaxis in fixation of closed long bone fractures showed no significant difference in the risk of wound infection between single and multiple perioperative doses. However, the risk ratio range was wide despite the inclusion of over 3,800 patients.

Prolonged antibiotic prophylaxis can increase the risk of acquisition of MRSA. In a study of patients who had free flap reconstructions of defects following excision of head and neck lesions, one group was given a five-day antibiotic course and the other a one-day course. Of 64 patients, 17 (27%) developed an infection with MRSA, all acquired after operation. The median hospital admission was longer for patients who acquired MRSA (p = 0.005). There were significantly fewer patients with wounds infected by MRSA in the one-day group (4/33 compared with 13/31, p = 0.01).

Therefore, when formulating antibiotic prophylaxis policies, regimens should be limited to a single dose or single day. The evidence should be liberally cited. If controversy remains then gentle persistence will eventually bear fruit.

Endocarditis risks

The issue concerning prevention of endocarditis following dental or surgical procedures has raised more fundamental questions. For 50 years successive guidance documents have recommended antibiotics prophylaxis to reduce the chance of bacteraemia associated with dental or surgical procedures causing endocarditis in patients with valvular lesions. This advice has depended on experience derived in animal models.

Clinical trials have not been possible because of the rarity of the condition and most evidence has come from case control studies. Bacteraemia during a procedure may be due to organisms found to cause endocarditis and which can be eradicated by antibiotics. The use of antibiotics, however, requires prophylaxis actually being effective in preventing endocarditis.

However, advisory bodies have now recognised that endocarditis is more likely to result from random bacteraemia due to tooth brushing than dental, gastrointestinal or genitourinary procedures. Antibiotic prophylaxis may then only prevent a small number of cases and the risk of adverse events due to the antibiotic is greater. Good oral hygiene is probably more important.

To stop recommending antibiotic prophylaxis to patients with valvular heart disease overturns 50 years of patient education. Most dental treatment results in bacteraemia but it is not possible to determine which procedures should have antibiotic cover because no data have been published that show bacteraemia affects the incidence of endocarditis.

The risk of endocarditis following a dental procedure is estimated to be very low, (between one in 95,000 and one in one million), so even if prophylaxis were highly effective the number of cases prevented would be very small. In a French study the risk in patients with prosthetic valves was one in 10,700 and one in 54,300 in patients with native valves while in the US the risks were one in 114,000 and one in 142,000 respectively. However, fatal anaphylaxis with penicillin occurs in
15–25 cases per million.

Guidelines for antibiotic use

The American guideline committee decided to recommend prophylaxis for those patients at highest risk, namely those with prosthetic cardiac valves, previous infective endocarditis, congenital heart disease (CHD), and cardiac transplantation recipients with cardiac valvulopathy. The Committee no longer recommended prophylaxis simply on the lifetime risk of endocarditis but a significant number of patients would continue to take prophylaxis.

"Prolonged antibiotic prophylaxis can increase the risk of acquisition of MRSA."

In contrast, in the UK NICE guidelines went a step further, having reviewed the same published evidence and concluded that antibiotic prophylaxis against endocarditis would not be recommended for any surgical or dental procedure unless there was active infection. The NICE committee was convinced that recommending antibiotics would result in a net loss of life. It suggested patients at risk of infective endocarditis should be given information on the risks and benefits of antibiotic prophylaxis, on maintaining good oral health and the risks of invasive procedures. Neither antibiotics nor chlorhexidine mouthwash were to be advised in future for dental or surgical procedures. Symptoms of infection should be rapidly investigated. If antibiotics were being given to treat infection they should be ones that cover the likely causes of endocarditis.

The result of such a change in advice in the UK has been repeated requests from cardiologists to dental surgeons to continue to use antibiotic prophylaxis as a precaution. Despite the lack of a consistent association between dental work and endocarditis, the adverse events and lack of evidence of efficacy, the feeling of some is that they prefer to err on the side of caution.

Prescribing antibiotics against the recommendations of an authoritative body has been raised as a problem for medicolegal defence lawyers and dentists have refused to comply with cardiologists' requests. Dentists have been advised by their defence bodies not to go against the NICE guidelines even if the patient requests it, unless they can produce a separate reasonable body of opinion. Cardiologists would have to prescribe antibiotics themselves prior to the dental procedure. Whilst it
is likely the situation will gradually resolve in favour of NICE guidance there will be a difficult period of transition.

Evidence-based guidelines are clearly the better path for health professionals than to use anecdotal experience. However, when the evidence itself is scant, clinical experience should not be disregarded. Unfortunately guidelines take on the force of law in a litigious health environment. When evidence base is sound it is unwise to ignore the guideline but even when it is not it is becoming increasingly difficult.

Research material has been referenced in this text. For full details please contact the editor, andrewtunnicliffe@spgmedia.com.