Education and debate

How do you choose antibiotic treatment?

Commentary: Resist jumping to conclusions

Commentary: A matter of good clinical practice

Commentary: Honesty is the best policy

How do you choose antibiotic treatment?

Leonard Leibovici, chairman ^a,  Ilana Shraga, physician ^a,  Steen Andreassen, reader ^b. 

^a Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv, 69978 Israel, ^b Department of Medical Informatics, Aalborg University, Aalborg, 9000 Denmark

Correspondence to: L Leibovici, Department of Medicine, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, 49100 Israel leibovic{at}post.tau.ac.il

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 scenariodeciding which drug to prescribe for a patient with urosepsiswhich illustrates the dilemmas in antibiotic prescribing.

	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 administrationthe time of the doctor, nurse, and pharmacistand 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.

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%.

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.

	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 advantagean 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

1.	Dolan JG, Bordley DR, Polito R. Initial management of serious urinary tract infection: epidemiological guidelines. J Gen Intern Med 1989; 4: 190-194[Medline].
2.	Esposito AL, Gleckman RA, Cram S, Crowley M, McCabe F, Drapkin MS. Community-acquired bacteremia in the elderly: analysis of one hundred consecutive episodes. J Am Geriatr Soc 1980; 28: 315-319[Medline].
3.	Jones GR, Lowes JA. The systemic inflammatory response syndrome as predictor of bacteraemia and outcome from sepsis. Q J Med 1996; 89: 515-522[Abstract].
4.	Meyers BR, Sherman E, Mendelson MH, Velasquez G, Srulevitch-Chin E, Hubbard M, Hirschman SZ. Bloodstream infections in the elderly. Am J Med 1989; 86: 379-384[Medline].
5.	Gransden WR, Eykyn SJ, Phillips I, Rowe B. Bacteremia due to Escherichia coli: a study of 861 episodes. Rev Infect Dis 1990; 12: 1008-1018[Medline].
6.	Moore RD, Smith CR, Lipsky JJ, Mellits ED, Lietman PS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100: 352-357.
7.	Berman JR, Zaran FK, Rybak MJ. Pharmacy-based antimicrobial-monitoring service. Am J Hosp Pharm 1992; 49: 1701-1706[Abstract].
8.	Standing Medical Advisory Committee, Sub-Group on Antimicrobial Resistance. The path of least resistance. London: Department of Health , 1998(www.doh.gov.uk/smac1.htm; accessed 11 May 1999.)
9.	Tomasz A. Multiple antibiotic resistant pathogenic bacteria. N Engl J Med 1994; 330: 1247-1251[Free Full Text].
10.	Morris JG, Shay DK, Hebden JN, McCarter RJ, Perdue BE, Jarvis W, et al. Enterococci resistant to multiple antimicrobial agents, including vancomycin: establishment of endemicity in a university medical center. Ann Intern Med 1995; 123: 250-259[Abstract/Free Full Text].
11.	Go ES, Urban C, Burns J, Kreiswirth B, Eisner W, Mariano N, et al. Clinical and molecular epidemiology of acinetobacter infections sensitive only to polymyxin B and sulbactam. Lancet 1994; 344: 1329-1332[Medline].
12.	Burwen DR, Banerjee SN, Gaynes RP. Ceftazidime resistance among selected nosocomial Gram-negative bacilli in the United States. National nosocomial infections surveillance system. J Infect Dis 1994; 170: 1622-1625[Medline].
13.	Ballow CH, Schentag JJ. Trends in antibiotic utilization and bacterial resistance. Report of the National Nosocomial Resistance Surveillance Group. Diagn Microbiol Infect Dis 1992; 15(suppl 2): S37-S42.
14.	Chow JW, Fine MJ, Shlaes DM, Quinn JP, Johnson MP, Ramphal R, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med 1991; 115: 585-590.
15.	Courcol RJ, Pinkas M, Martin GR. A seven year survey of antibiotic susceptibility and its relationship with usage. J Antimicrob Chemother 1989; 23: 441-451[Abstract/Free Full Text].
16.	Gerding DN, Larson TA, Hughes RA, Weiler M, Shanholtzer C, Peterson LR. Aminoglycoside resistance and aminoglycoside usage: ten years of experience in one hospital. Antimicrob Agents Chemother 1991; 35: 1284-1290.
17.	Leibovici L, Samra Z, Konigsberger H, Drucker M, Ashkenazi S, Pitlik SD. Long-term survival following bacteremia or fungemia. JAMA 1995; 274: 807-812[Abstract].
18.	Leibovici L, Shraga I, Drucker M, Konigsberger H, Samra Z, Pitlik SD. The benefit of appropriate empirical antibiotic treatment in patients with bloodstream infection. J Intern Med 1998; 244: 379-386[Medline].
19.	Holloway JJ, Craig CR, Moore RD, Feroli ER, Lietman PS. Comparative cost-effectiveness of gentamycin and tobramicin. Ann Intern Med 1984; 101: 764-769.
20.	Eisenberg JM, Koffer H, Glick HA, Connell ML, Loss LE, Talbot GH, Shusterman NH, Strom BL. What is the cost of nephrotoxicity associated with aminoglycosides? Ann Intern Med 1987; 107: 900-909.
21.	Garrelts JC, Horst WD, Silkey B, Gagnon S. A pharmacoeconomic model to evaluate antibiotic costs. Pharmacotherapy 1994; 14: 438-445[Medline].
22.	Leibovici L, Shraga I. Side-effects of antibiotic drugs: Meta-analysis of observational data. J Hosp Infect 1998; 40(suppl A): W4C.
23.	Perl TM, Dvorak M, Hwang T, Wenzel RP. Long-term survival and function after suspected gram-negative sepsis. JAMA 1995; 274: 338-345[Abstract].
24.	Quartin AA, Schein RMH, Kett DH, Peduzzi PN. Magnitude and duration of the effect of sepsis on survival. JAMA 1997; 277: 1058-1063[Abstract].
25.	Mark DB. Economic analysis methods and endpoints. In: Califf RM, Mark DB, Wagner GS, eds. Acute coronary care in the thrombolytic area. 2nd ed. St Louis: Mosby Year Book, 1995:167-182.
26.	Møller JK. Antimicrobial usage and microbial resistance in a university hospital during a seven-years period. J Antimicrob Chemother 1989; 24: 983-992[Abstract/Free Full Text].
27.	Sundman K, Arneborn P, Blad L, Sjoberg L, Vikerfors T. One bolus dose of gentamycin and early oral therapy versus cefotaxime and subsequent oral therapy in the treatment of febrile urinary tract infection. Eur J Clin Microbiol Infect Dis 1997; 16: 455-458[Medline].
28.	Burke JP. Antibiotic resistancesqueezing the balloon? JAMA 1998; 280: 1270-1271[Free Full Text].
29.	Rahal JJ, Urban C, Horn D, Freeman K, Segal-Maurer S, Maurer J, et al. Class restriction of cephalosporin use to control total cephalosporin resistance in nosocomial klebsiella. JAMA 1998; 280: 1233-1237[Abstract/Free Full Text].
30.	Pestotnik SL, Classen DC, Evans RS, Burke JP. Implementing antibiotic practice guidelines through computer-assisted decision support: clinical and financial outcomes. Ann Intern Med 1996; 124: 884-890[Abstract/Free Full Text].
31.	Evans RS, Classen DC, Pestotnik SL, Lundsgaarde HP, Burke JP. Improving empiric antibiotic selection using computer decision support. Arch Intern Med 1994; 154: 878-884[Abstract].
32.	Leibovici L, Gitelman V, Yehezkelli Y, Poznanski O, Milo G, Paul M, Ein-Dor P. Improving empirical antibiotic treatment: Prospective, nonintervention testing of a decision support system. J Intern Med 1997; 242: 395-400[Medline].

(Accepted 18 February 1999)

Commentary: Resist jumping to conclusions

Stephen G Pauker, professor,  Michael Rothberg, fellow in clinical decision making. 

New England Medical Center, Box 302, 750 Washington Street, Boston, MA 02111, USA

Correspondence to: S G Pauker stephen.pauker{at}es.nernc.org

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 perspectivefor 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 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).

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,²⁵ 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

1.	Goldratt E. The goal. Great Barrington, MA: North River Press , 1992.
2.	Chow JW, Fine MJ, Shlaes DM, Quinn JP, Hooper DC, Johnson MP, et al. Enterobacter bacteremia: clinical features and emergence of antibiotic resistence during therapy. Ann Intern Med 1991; 115: 585-590.
3.	Levy SB. The antibiotic paradox: how miracle bugs are destroying the miracle. New York: Plenum , 1992.
4.	Alliance for the Prudent Use of Antibiotics (www.healthsci.tufts.edu/apua/apua.html; accessed 11 May 1999.)
5.	Weiner J, Quinn JP, Bradford PA, Goering RV, Nathan C, Bush K, Weinstein RA. Multiple antibiotic resistent klebsiella and Escherichia coli in nursing homes. JAMA 1999; 281: 517-523[Abstract/Free Full Text].

Commentary: A matter of good clinical practice

Julius R Weinberg, consultant epidemiologist,  Brian I Duerden, deputy director. 

Public Health Laboratory Service, London NW9 5EQ

Correspondence to: Professor Duerden bduerden{at}phls.nhs.co.uk

The scenario presented by Leibivici and colleagues illustrates classic dilemmas of clinical practicehow 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 aspecttheir 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 usewhether 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.

Commentary: Honesty is the best policy

Margaret A Drickamer, associate professor. 

Yale University School of Medicine, 20 York Street, New Haven, CT 06504, USA

Drickamer{at}med.va.gov

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."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.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

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

1.	American College of Physicians. Ethics manual. 4th ed. Ann Intern Med 1998; 128: 576-594[Abstract/Free Full Text].
2.	Sulmasy DP. Physicians, cost control, and ethics. Ann Intern Med 1992; 116: 920-926.
3.	Hall MA, Berenson RA. Ethical practice in managed care: a dose of realism. Ann Intern Med 1998; 128: 395-402[Abstract/Free Full Text].