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. 1999 Jun 12;318(7198):1614–1618. doi: 10.1136/bmj.318.7198.1614

How do you choose antibiotic treatment?

Leonard Leibovici a, Ilana Shraga a, Steen Andreassen b
PMCID: PMC1115976  PMID: 10364128

Even the most common problems in antibiotic treatment do not have simple solutions. Choosing one antibiotic drug from among several candidates entails balancing the benefits and the detriments associated with each. In this article we engage the reader in a common scenario—deciding which drug to prescribe for a patient with urosepsis—which illustrates the dilemmas in antibiotic prescribing.

Summary points

  • In choosing antibiotic treatment, the benefits and detriments associated with each drug should be compared

  • Cost effectiveness analysis can serve as a framework for such a comparison

  • The benefit associated with appropriate antibiotic treatment may be so great that drug costs and side effects become secondary considerations

  • The development of future resistance is the major concern

  • In choosing antibiotic treatment, doctors have to choose between the interests of present and future patients

Scenario

You are a hospital doctor. An 83 year old man is admitted to your department at 2 am because of fever (temperature 38.7°C), dysuria, and chills. On the basis of clinical findings and microscopic examination of his urine, you decide that the patient has a severe urinary tract infection and needs intravenous antibiotic treatment.

In people of his age with urinary tract infection, the most common pathogens are Escherichia coli (about 60% of cases), Proteus mirabilis (10%), and Klebsiella pneumoniae (10%).1,2 The susceptibility of common pathogens to a range of antibiotics is reported yearly by the microbiology laboratory at your hospital. From this you calculate that ampicillin will cover 40% of pathogens, second generation cephalosporins 75%, gentamicin 92%, third generation cephalosporins 95%, and imipenem 100%.

You believe that empirical antibiotic treatment matching the in vitro susceptibility of the pathogen will afford the patient the best chance of survival and an uneventful recovery.3–5 However, you have been told repeatedly by the head of the department that the budget is limited and third generation cephalosporins and imipenem are disproportionately expensive. About 10% of patients treated with gentamicin develop nephrotoxicity, and a similar percentage develop mild ototoxicity. Severe side effects occur in fewer than 1% of patients taking gentamicin. You are aware that advanced age is a risk factor for nephrotoxicity.6 On the other hand, within 48 hours you may be able to change to another drug, given the in vitro susceptibility of the pathogen.

The thought that a healthy and active 83 year old man will need haemodialysis because of a drug that you have prescribed is frightening, so you decide to order a second generation cephalosporin. Still, you are not altogether happy about the fact that you have reduced the antibiotic coverage by 7%-15% because of your concern about the high costs and fear of side effects associated with other antibiotics. You wish that the balance of benefits and detriments of antibiotic drugs could have been weighed at leisure somewhere else and that you had evidence based guidelines to help you make a choice.

Deliberations of the drug committee

First meeting

Meanwhile, the drug committee in your hospital is convened to do exactly that. The heads of the infectious diseases unit and pharmacy and the manager of the hospital haggle over which antibiotic drug should be advised for an elderly patient with suspected urosepsis. The pharmacist shows the others a list of drug prices (table 1). The costs of administration—the time of the doctor, nurse, and pharmacist—and the cost of intravenous access should also be taken into account. For aminoglycosides, determination of blood concentrations and monitoring of kidney function should be included too.

Table 1.

Cost of 1 day’s treatment with antibiotics

Drug Cost in $US (£)
Ampicillin 12 (7)
Gentamicin 14 (8)
Cefotaxime  92 (56)
Cefuroxime  76 (46)
Imipenem 110 (67)
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The hospital manager is adamant that either gentamicin or ampicillin must be chosen. Antibiotics accounted for 50% of the pharmaceutical budget last year,7 and the hospital’s financial position is precarious. However, the specialist in infectious diseases claims that with such a low rate of coverage, ampicillin is not a feasible option. And another consideration must be taken into account—the resistance of Gram negative pathogens in the hospital is rising steadily, probably induced by consumption of antibiotics.8 In a few years the hospital may face pathogens that are resistant to all drugs,9–11 and patients may pay dearly in terms of increased mortality and morbidity. Third generation cephalosporins are major culprits12–15; imipenem probably less so. However, the increase in resistance to aminoglycosides is slow.16

The hospital manager wants to know what to choose—which is the most cost effective drug. The others tell him that the answer lies in a cost effectiveness model, but both the data and structure for a cost effectiveness analysis are lacking.

An attempt at cost effectiveness analysis

A study on long term survival after bacteraemia provides some of the data needed for cost effectiveness analysis.17 In this study, 1234 patients with Gram negative infections of the bloodstream were followed for a median of 17 months. The influence on survival of appropriate empirical antibiotic treatment, functional capacity, age, hospital acquired infection, septic shock, neutropenia, malignancy, and serum albumin and creatinine concentrations were modelled using Cox regression analysis (unpublished data).17,18 Empirical antibiotic treatment was considered appropriate if the infecting pathogen was subsequently found to be susceptible in vitro to the drug administered. The multivariable adjusted median survival of patients given appropriate empirical antibiotic treatment was longer by 12.6 months than that of patients given inappropriate treatment, and the hospital stay was shorter by one day. (The cost of a one day stay in our hospital is about $350 (£213).) The susceptibilities of the 1234 isolates to antibiotic drugs were as follows: ampicillin 43%, cefuroxime 61%, cefotaxime 74%, gentamicin 77%, and imipenem 98%.

The costs of the drug, administration, monitoring, and side effects 19–22 for the five drugs in our hospital are given in table 2. Thus, the marginal cost of one life year for preferring imipenem to ampicillin as empirical treatment $48 (£29), the marginal cost for preferring imipenem to cefuroxime and cefotaxime is zero, and the marginal cost for preferring imipenem to gentamicin is $253 (£154). These costs depend strongly on the benefit of empirical treatment. Confidence in the survival data is increased by the fact that similar survival curves have been reported by two other groups.23,24 Even in patients with the worst prognosis (those with malignancy or septic shock, or those who are very old) appropriate empirical antibiotic treatment bought more than one month of life. Assuming that we buy only one month of life, the cost of one life year caused by preferring imipenen over the other drugs is still less than $1000 (£609). The figure is lower by an order of magnitude than the cost of gaining one life year with other established treatments—$20 000 (£12 200) for treating severe hypertension or $35 000 (£21 350) for haemodialysis.25

Table 2.

Cost of 2 days’ empirical treatment. Costs given in $US (£)

Antibiotic Drug and administration Side effects Monitoring Total cost
Ampicillin 42 (26) 70 (43) 0 112 (68)
Gentamicin 38 (23) 126 (77) 18 (11) 182 (111)
Cefotaxime 214 (130) 76 (46) 6 (4) 296 (180)
Cefuroxime 182 (111) 60 (36) 6 (4) 248 (151)
Imipenem 250 (152) 76 (46) 6 (4) 332 (202)
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It turns out that, taking into account only the cost of the drug, its administration, and side effects, we should prescribe the broadest spectrum antibiotic available for every patient suspected of harbouring a severe bacterial infection. In other words, the only valid argument against maximum antibiotic coverage for every patient is the development of future resistance.

Subsequent discussion

The infectious diseases specialist says that if this analysis is true the rates of development of antibiotic resistance in the hospital should be looked at first, and an attempt should be made to correlate these with the consumption of antibiotics. In hospitals with low rates of resistance, and for some drugs, these relations are almost linear.26 Unfortunately, this is not the case in your hospital. No model is available from which to extrapolate resistance from the consumption of antibiotics, nor is the cost of the future resistance known. In addition, antibiotic resistance will result in an increase in morbidity and mortality, because more patients will be given inappropriate treatment. The specialist agrees to produce a ranking of the antibiotics in terms of induction of future resistance.

The manager says that many patients are treated with antibiotic drugs. That cost effectiveness analysis might result in a policy that will be costly during the next year or so, yet save money later. But even if such a policy makes sense, the budget for the next year might not allow it.

The specialist in infectious diseases states that, taking all this into account, he would advise gentamicin as empirical treatment for severe urinary tract infections but would switch on day 2 or day 3 to another drug, probably an oral quinolone, depending on the in vitro susceptibilities of the pathogen isolated.27

However, the pharmacist believes that this single recommendation will not make much of a difference. The drug committee has discussed one simple infection. What about other sites of infection? How are the recommendations to be implemented? Will the implementation achieve its goals?

Back to the dilemma

Two days after admission your patient is doing well. The deliberations of the drug committee are brought to your attention. You believe that the explicit balance of antibiotic treatments and the introduction of data are helpful, but you are uneasy about having one simple guideline to cover such a diversity of patients. It clashes with your belief that treatment should be tailored to the patient. You are not surprised that empirical treatment matching the in vitro susceptibility of the pathogen affords a patient with severe infection a better chance of survival. (Doctors work daily on that assumption.) But you wonder whether prescribing a drug that affords less than the maximum coverage is the right thing to do. It may well slow down the development of resistance and give future patients (to whom you have a duty too) a better chance for an uneventful recovery ... but your main duty is to your present patient. How do you balance the two duties? Furthermore, you were taught that major medical decisions should be taken together, by patient and doctor. What do you tell your patient?

Conclusions

Even the most common problems in antibiotic treatment do not have simple solutions. Choosing an antibiotic drug from among several candidates (including no treatment) entails analysing the benefits and the detriments associated with each drug and balancing each one against the others. In this scenario, matching the in vitro susceptibility of the pathogen was associated with substantial advantage—an advantage so great that the cost of the drug and side effects were rendered secondary considerations. However, the development of future resistance remained the major concern.

We need a framework that enables us to balance the benefits and detriments of antibiotic drugs in any given situation. Cost effectiveness analysis can provide such a framework, but it must take into account the consequences of future resistance. However, even in the absence of a complete framework and complete data, approximations can be usefully made.

It is doubtful if simple guidelines are successful in improving antibiotic usage.28,29 Bedside computerised decision support tools, based on local data, may perform better and be more acceptable to the doctor.30–32

Reaching an agreement on antibiotic policy is difficult, even given the results of a cost effectiveness analysis. The considerations of the patient, the doctor, and the policymaker may differ. The important decision in antibiotic treatment turns out to be a choice between present and future patients.

Footnotes

Funding: Supported in part by a grant from the Telemetics Program of the European Union (HC-REMA).

Competing interests: None declared.

References

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BMJ. 1999 Jun 12;318(7198):1614–1618.

Commentary: Resist jumping to conclusions

Stephen G Pauker 1, Michael Rothberg 1

We practise in a world of limited resources. Because most of the decisions doctors make affect health expenditure, we must think cost effectively, even about individual patients. The inherent conflict between things optimal for the patient before us at the moment and for other patients (those whom we are about to treat, whom other clinicians treat, patients untreated, and future patients) is not only the stuff of ethics, philosophy, and politics, but must also be addressed at the bedside and by local policy committees.

The first step in performing a cost effectiveness analysis is to specify its perspective—for example, undertaken from the point of view of the patient, the insurer, a particular hospital department, or society. Different perspectives may lead to different conclusions. Constituencies can arrive at policies that optimise their local objectives or measures while harming the global objective of the organisation.1-1 Was that the problem driving the pharmacist and the hospital manager described by Leibovici and colleagues, so that they focused largely on the cost of the antibiotic? Did they underplay the consequences of choosing an inappropriate antibiotic because their own performance was measured largely by their ability to control costs?

Perhaps the greatest advantage of formal analyses is that they are explicit, reveal their underlying assumptions, and expose flaws in logic and reasoning. They allow us to ask, “What if?” What if the expected gain in choosing the appropriate antibiotic an 83 year old man were far lower than the 12.6 months’ gain for the average patient? What if we considered combination therapy with two relatively inexpensive drugs, say ampicillin and gentamicin, as is common practice in some other settings.

In the scenario of Leibovici and colleagues, the only relevant comparison seems to be between gentamicin and imipenem; the other antibiotics provide lower survival at higher cost. Imipenem would be “appropriate” 21% more often, at an added cost of $77 (£47), including the cost of the prolonged stay for insensitive organisms. The ratio of $367 (£224) per additional patient receiving appropriate treatment can be converted into a cost effectiveness ratio, provided we know by how much the proper antibiotic prolongs survival. If the 12.6 month median applies to 83 year old men with urosepsis, then using imipenem would cost $347 (£211) per year of life saved, a bargain by any measure. Analyses such as these allow decisions to be tailored to individual patients and circumstances (table).

Table.

Cost effectiveness analysis of antibiotics. Costs are given in $US (£)

Antibiotic Sensitivity Costs
Total costs Marginal cost Benefits
Marginal cost effectiveness ($ (£)/year)
Drug and administration Side effects Monitoring Extra hospital day* Survival benefit (years) Marginal survival (years)
Gentamicin 0.77 38 (23) 126 (77) 18 (11) 81 (49) 263 (160) — 0.81 — —
Ampicillin 0.43 42 (26) 70 (43) 0 200 (122) 312 (190) 49 (30) 0.45 −0.36 Dominated†
Imipenem 0.98 250 (152) 76 (46) 6 (4) 7 (4) 339 (207) 28 (17) 1.03 0.22 347 (211)
Cefuroxime 0.61 182 (111) 60 (36) 6 (4) 137 (83) 385 (234) 46 (28) 0.64 −0.17 Dominated†
Cefotaxime 0.74 214 (130) 76 (46) 6 (4) 91 (55) 387 (236) 3 (2) 0.78 −0.03 Dominated†
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1-150

Cost of 1 day in hospital=$350 (£213), this is calculated as 1 minus sensitivity. 

1-151

Dominated=higher costs and lower survival, which suggests option should be rejected. 

One cannot help but compare the explicitness of Leibovici’s analysis when considering the present patient to the apparent abandonment of that approach when considering the effects of antibiotic resistance. The recommendation of the infectious disease specialist changed from imipenem to gentamicin, with nary a speck of his logic revealed. Although the Leibovici’s committee did not have extensive data about the relation between antibiotic use and future antibiotic resistance immediately available,1-2−1-5 they might have considered how these data could be incorporated explicitly into a model, rather than jumping to the conclusion that future antibiotic resistance is the major concern and that the underlying trade off is between present and future patients. Perhaps Leibovici’s conclusion is correct, but the logic is not substantiated here.

References

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BMJ. 1999 Jun 12;318(7198):1614–1618.

Commentary: A matter of good clinical practice

Julius R Weinberg 1, Brian I Duerden 1

The scenario presented by Leibivici and colleagues illustrates classic dilemmas of clinical practice—how to practise good medicine when there is imperfect information and how to balance the responsibilities of the doctor to the individual patient and to the community. These issues and the relation between cost and efficacy are of concern in many areas of practice, but antimicrobial drugs differ from other treatments in one important aspect—their use in one patient may reduce their efficacy in another patient because of the selection of resistant organisms. Leibovici and colleagues show that the benefit from appropriate antibiotic treatment of severe infection, as determined by cost effectiveness analysis, is so large that the drug costs and side effects are irrelevant. The development of future resistance remains as the major concern in selecting antibiotic treatment.

However, this does not mean that a clinician’s decisions over the choice of antibiotic have a different basis from those made about other treatment options. Decisions are based on the answers to the following questions:

  • Is this the right drug for the condition?

  • Is the balance of likely benefit against harm appropriate in this patient?

  • Given the cost of the drug and the prevailing economic conditions, is its prescription appropriate?

  • Finally, for an antibiotic, is there an equally good (in clinical and economic terms) option which would be less likely to promote resistant organisms?

Development of future resistance is easy to predict ... it is inevitable. However, which resistances will emerge, and why, is poorly understood, as are the strategies to prevent a particular resistance or the likelihood of its development. Resistance may even arise to antibiotics which are not in use if cross resistance is generated by a related compound. Therefore, in the absence of direct evidence for using a particular drug, and since all antibiotic use generates resistance, the most prudent approach is to maximise the appropriate use of antibiotics and minimise their inappropriate use—whether that be use when they are not indicated, or in the wrong dose, or the wrong regimen. As this is good clinical practice, there is little conflict between good clinical medicine and good public health practice.

It would be difficult and wrong to sustain an argument that antibiotics should be withheld when clinically appropriate because of a potential future risk to others. It would also be difficult to sustain an argument on any grounds, clinical or public health, that clinicians should continue to prescribe antibiotics when there is no clinical indication, thus putting their patient at risk of unwanted side effects and the population at risk of increased resistance.

The recognition that the clinician has a duty to the health of the wider population as well as to the individual patient is welcome. Doctors who fail to notify infection, and laboratories that fall to report to public health authorities, are failing in their duty of clinical care. Good patient care and good public health medicine are not in conflict, but follow from the same good clinical practice.

BMJ. 1999 Jun 12;318(7198):1614–1618.

Commentary: Honesty is the best policy

Margaret A Drickamer 1

If we accept the assumptions made in the conclusion of the article by Leibervici and colleagues that antibiotic treatment with the “super antibiotic” is both economical and in the best interest of the patient, we are left with the question of whether the choice of antibiotics should be influenced by the greater good of the community or the best interests of the patient. Decisions about subjugating the good of the individual to the greater good of society are common for many professional people, from generals to teachers. However, Leibovici and colleagues ask whether this also holds true for doctors.

The argument for the doctor’s role as an agent for the greater good of the public is that the doctor is educated and empowered (and paid) by the community to protect its interests. The American College of Physician’s Ethics Manual states, “All physicians must fulfill the profession’s collective responsibility to advocate the health and well-being of the public.”3-1 Doctors are to “use all health-related resources in a technically appropriate and efficient manner.” Since it is in the best interest of the public health that certain antibiotics be used with circumspection, the medical profession is left with two options: each individual doctor must take responsibility for the judicious use of antibiotics in the public interest; or individual doctors will have to give up some of their autonomy to allow another authority (a hospital board or epidemiologist) to make these decisions.

Tenets governing the doctor-patient relationship which would be violated by such an act include:

  • The doctor as advocate for the patient

  • The doctor’s accountability for the patient’s wellbeing

  • The doctor’s duty to be truthful (which would includes full disclosure of therapeutic options)

  • The trust that the patient has that the doctor will do what is right.

There are two related examples of similar conflicts of role. The doctor has been in the position of breaking confidentiality with patients in reporting contagious disease in order to ensure the public health. Also, in a system with a capped budget for health related needs, decisions frequently need to be made about the distribution of resources which limit doctors’ ability to be advocates for their patients.3-2 More controversial is the instance in which doctors are asked to limit their advocacy for their patients so that an organisation may make a profit.3-3

Is a doctor justified in giving a patient second best or probably good enough treatment for the sake of the greater good? The answer is probably “Yes.” There are accepted precedents for such a decision, and it is considered part of the doctor’s duty to serve society. However, so that doctors do not feel that as advocates and advisers they have broken trust with their patients, they should inform patients of the choice, assuring them that they will be monitored carefully and antibiotics will be changed if the need arises. Patients and families are very understanding of these decisions and can continue to trust the honesty of their doctor and his or her commitment to do what is in their best interest.

References

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