What’s stopping antibiotic de-escalation therapy?

Posted 4th September 2009 in Articles, Therapeutic Area | 3 comments

Peter West

Wyeth Europa

Everyone seems to agree that antibiotic de-escalation therapy seems to make sense. The big question is therefore why aren’t we doing it?

Antibiotic de-escalation therapy is the practice of using more powerful antibiotics, earlier in treatment, for a short period of time – and then switching to a less powerful antibiotic once the infection is accurately diagnosed and under control. One could argue that the concept of “hit hard – hit fast” is not new. Paul Ehrlich described something similar to this with his “magic bullet” theory at the turn of the last century.

Over recent years the momentum appears to have grown and studies have demonstrated that early intervention with appropriate antibiotic therapy saves lives and reduces morbidity.

At a recent international congress I was amongst an audience of clinicians where the chairman was seeking individual views on de-escalation. The responses were consistent to the point of being unanimous – de-escalation makes good sense and should be practiced.

But frequently, it isn’t. So why is this the case?

I think that part of the conundrum is the disease process itself, which frequently is one of escalation. A patient presenting on a ward in hospital may not initially have a “serious” infection. They may be admitted for something quite different, like a broken limb, and have no infection at all. But within a matter of days this situation can change and, in particular for the more elderly complicated patients with underlying diseases/co-morbidities, the situation can deteriorate very rapidly.

“…de-escalation makes good sense and should be practiced.”

For example: It would seem unnecessary, foolish even, to commence therapy for a mild chest infection with a very powerful antibiotic when the clinical signs and symptoms do not warrant this. But in some patients what appears to be a mild infection can progress to a more serious clinical situation.

Diagnostic techniques in microbiology have still not advanced to the stage where early detection of a causative pathogen can be easily made. It remains the case that a 48 hour period will lapse before microbiological results can be obtained. So what happens then?

The results may reveal not one, but several bacteria, are present. This then becomes a sort of bacterial “whodunit”? Are we witnessing a genuine polymicrobial infection or are some of those bacteria simply colonizing and not infecting the patient? Which one is the real culprit and how should we target therapy to deal with it? In some cases the microbiological results reveal…nothing!

So the situation is complex.

Consideration of the host (patient history, site of infection), the environment (the level of bacterial resistance in that particular unit) and the suitability of available therapy (efficacy and tolerability of the antibiotics at ones disposal) all play a major part in selecting the most appropriate therapy. Even with microbiological results we may still be dealing with an empiric situation.

In some cases the patient will have already received antibiotic therapy but may not be responding clinically. Studies again suggest that in such a situation it is imperative to select an antibiotic agent from a different class. But how well is this understood or practiced?

Initial therapy with beta-lactam antibiotics, such as penicillin based compounds or cephalosporin is still commonplace in many units. If initial therapy with these agents is failing then the evidence demands a change of antibiotic class. But frequently, in deteriorating clinical situations, clinicians, in pursuit of de-escalation, may turn to carbapenem type agents. However, carbapenems are also beta-lactam antibiotics and so this would appear to go against the tide of evidence.

“…the increase of carbapenemases is a worrying development and resistant strains of klebsiella are becoming a major concern across Europe.”

In recent years we have also witnessed an increasing and disturbing level of resistance to some carbapenem type agents – the increase of carbapenemases is a worrying development and resistant strains of klebsiella are becoming a major concern across Europe. Concerns about increases in carbapenem type resistance are only heightened by the availability of new carbapenem type agents and the possibility of the development of cross-resistance.

The pipeline of new antibacterials in development has diminished over recent years – particularly those agents with activity against gram negative bacteria. The regulatory environment is becoming more demanding, and regulators would prefer to see clear evidence of “superiority” over existing agents, rather than “non-inferiority”. But this is time-consuming and costly to achieve. It may not even be possible.

The question arises whether a new agent, albeit only with evidence of non-inferiority rather than superiority, is still a valuable asset in terms of reducing selection pressure on existing agents? Most clinicians would feel that this is a valid argument.

All of this amounts to a very difficult decision making process and it is perhaps not surprising that de-escalation is easy to agree on, but harder to deliver in practice.

So where do we go from here?

About the author:

Peter West is Senior Marketing Director, Infectious Diseases at Wyeth Europa, based in the UK.

For enquiries, please email westp2@wyeth.com

User Comments

KBrockbank

4th September 2009, 16:48

Do you think that health authroity strategies to reduce prescribing of costly, newer antibiotics; which is counter to the de-escalation startegy play a significant part in real clinical practice as opposed to theories easily espoused in the context of a conference?
Also, is it possible that a history of "prophylactic" use of antibiotics in primary care has mede clinicians more cautious of their use of newer antibiotics?

petewest

26th September 2009, 07:35

KB - thank you for raising these questions. I had waited a while before replying in the hope that others may weigh in with their views. Perhaps they will add to my comments which follow:

in answer to your questions..

I do not think that health authority strategies to reduce prescribing of costly, newer antibiotics are impacting significantly upon de-escalation practice. First, I think that, in the main, antibiotics are not "expensive" drugs, compared say to some specialist drugs in other areas, like oncology for example. I'm not aware that antibiotics have been singled out in this way for special attention. Having said that, any new medicine has to be priced in such a way as to gain market access and reimbursement. So cost, or more accurately, "price" can be a factor, but usually at the point of market access - not at the bedside. This is an important distinction to make.

A clinician, at the bedside, witnessing an infected patient deteriorating before his/her eyes, has to make a decision on treatment. It is highly likely that the patient will be on some kind of antibiotic already. Quite commonly the patient will be on some type of antibiotic that covers a wide spectrum of bacteria. If the patient is not responding, and particularly if they are rapidly worsening, the prescribing decision will be based on choosing an antibiotic that provides a greater chance of survival. Given the limited choice of antibiotics available and the clinical deterioration of the patient and the need to act rapidly - cost does not come into it in this situation.

Re your second point: I suspect you are referring to "overuse" of antibiotics in primary care rather than "prophylaxis" as such? Because prophylaxis suggests giving an antibiotic to a patient in a state of non-infection, to prevent an infection from occurring - and I'm not aware this happens in primary care.

I think that clinicians, whether primary or secondary care based, are much more aware of the problems with overuse of antibiotics these-days. Certainly in the UK there has been a considerable effort to avoid primary care prescriptions of antibiotics for trivial complaints or things like sore throat which is just as likely to be viral as bacterial. But no, actually I don't think this increased caution is the thing that is getting in the way of antibiotic de-escalation in hospital either.

I think we are talking about habit above all else. There are certain antibiotics which clinicians become familiar with. In a mild to moderate infection a simple penicillin or penicillin combination, or quinolone may well be sufficient. If the condition is more serious than that, or if there are underlying complications, a more heavyweight antibiotic could be selected. To some extent there is perfect logic in this approach. Why take a sledgehammer to crack a walnut?

The difficulty lies in knowing whether you are dealing with a walnut or something more significant. To answer that question requires more attention to be paid to the patient's "risk factors" when selecting empirical antibiotic therapy and being mindful of the local bacterial resistance patterns - which may be specific to a particular unit within each hospital.

RSDM64

15th December 2009, 01:13

This concept has real significance to the respiratory field where clinical trial data seems to indicate an appropriately spaced profilactic use can reduce frequency and severity of COPD exacerbations and hence increase patient life span.

One of the real problems of using the weaker cheaper antibiotics is that in many cases it kills off only part of the pathogens, effectively dampening down the infection, leaving the remaining ones still there to recolonise.

To hit them hard and fast with a de-escalation approach would be more effective, as we know the efficacy of these more powerful drugs is less when introduced too late in the prescribing timeline.

However, in response to KBrocklebank's comments, I feel that health authority strategies to reduce prescribing of newer antibiotics is counter to the de-escalation strategy and unfortunately these strategies do play a significant part in clinical practice in primary care.