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Evolution of Antimicrobial Resistance:Impact on Antibiotic Use Didier Guillemot, M.D.,1 Anne Claude Crémieux, M.D.,2
and Patrice Courvalin, M.D.1
ABSTRACT
During the past 50 years, the permanent increase in bacterial resistance to antibi- otics has led to modifications in therapeutic recommendations. Despite evidence that an-timicrobial exposure of human populations is the most important driving force for thecontinuous increase in bacterial resistance, the studies of the impact of bacterial resistanceon antibiotic use have, during the past, focused on clinical efficacy of individual treatmentsrather than on collective control of resistance. There are current changes in this attitude,mainly in hospitals, probably because hospital prescribers have experienced the conse-quences of resistance on their patients. However, in the community such an awareness isnot likely to develop in the near future. Therefore, there is a need for public health decisionmakers to become more involved in prevention of the impact of resistance in antibiotic use.
KEYWORDS: Antimicrobial resistance, antibiotic use, therapeutic decision, drug
policy
Objectives: Upon completion of this article, the reader will be able to: (1) describe the problem of treating community and nosoco-
mial infections in the face of increasing prevalence of resistant pathogens; and (2) define collective strategies for maintaining an-
timicrobial efficacy in the hospital and in the community.
Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor
continuing medical education for physicians.
Credits: The University of Michigan designates this educational activity for a maximum of 1.0 hour in category one credits toward
the AMA Physicians Recognition Award.
Antimicrobial resistance has emerged as a major ceptible organisms.4 Repeated warnings have been is- public health concern worldwide. During the past sued on the development of bacterial resistance to an- decades, despite the continuous marketing of new an- tibiotics and the related threats to the effectiveness of tibiotics, antimicrobial resistance has increased steadily.
available antibiotics. Many researchers have predicted In hospitals, roughly 70% of bacterial pathogens are re- doom and gloom scenarios, claiming that a considerable sistant to at least one antibiotic.1 Patients with infec- proportion of infections will become steadily more dif- tions due to resistant organisms are likely to require more and longer hospital stays,2 and to die.3 Furthermore, the Although estimation of risks associated with the collective economic cost of infections with resistant bac- use of antibiotics based on a single bacterium–resistance teria seems to be much higher than for those with sus- mechanism model cannot be strictly extrapolated to an- Hospital-Acquired Pneumonia; Editor in Chief, Joseph P. Lynch, III, M.D.; Guest Editor, Mark J. Rumbak, M.D. Seminars in Respiratory andCritical Care Medicine, volume 23, number 5, 2002. Address for correspondence and reprint requests: Patrice Courvalin, M.D., Unité des AgentsAntibactériens–Centre National de Reference des Antibiotiques, Institut Pasteur, 25–28 rue du Dr. Roux, 75724 Paris Cedex 15. Email:[email protected]. 1Unité des Agents Antibactériens–Centre National de Reference des Antibiotiques, Institut Pasteur, Paris, France; 2HopitalBichat–Faculté de Médecine Bichat Claude Bernard, Paris, France. Copyright 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue,New York, NY 10001, USA. Tel: +1(212) 584-4662. 1069-3424,p;2002,23,05,449,456,ftx,en;srm00174x.
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 23, NUMBER 5 2002
other pair, the causal relationship between exposure of classes of drugs that are not related structurally and dif- human populations to antibiotics and the progression of bacterial resistance to the same molecules should be Co-resistance is due to the presence in the same considered an established fact. Numerous studies have bacterium of several mechanisms, each conferring resis- demonstrated this association in both the hospital6 and tance to an antibiotic class. The corresponding genes are often part of the same replicon (chromosome or plas- Thus, there are two main reasons for optimizing mid), which results in co-dissemination—vertically to antibiotic use: (1) the increased recognition of inadequate the progeny if the resistance determinants are located in antimicrobial treatment both in the community and in the chromosome; both vertically and horizontally by hospital settings and its potential impact on the outcome lateral gene transfer for genes located on self-transfer- of severe infections (individual approach), and (2) evi- able plasmids or conjugative transposons. In the case of dence and general consensus in the medical community S. pneumoniae the multidrug-resistant (to penicillins, that resistance to antimicrobial drugs is clearly linked to macrolides, tetracycline, chloramphenicol, trimethoprim, the consumption of antibiotics (collective approach).
and sulfonamides) strains have the resistance genes sta- For the past 50 years, evolution of resistance has bilized in their chromosome. Because dissemination of led to modifications in the use of antibiotics, but there is pneumococci is clonal, a few distinct bacteria account no evidence that these modifications, even the more re- for a worldwide evolution of this species toward mul- cent ones, have combined optimization in clinical effi- cacy (individual approach) and delay in the progression In gram-negative bacteria, such as Klebsiella of antimicrobial resistance in human pathogens.
pneumoniae, P. aeruginosa, and Acinetobacter spp., a veryelegant system of gene capture and expression, namedintegron, is responsible for co-resistance to multipledrug classes.14,15 The net result of these genetic elements HOW ANTIBIOTIC USE SHOULD BE
is to assemble and express in a coordinated fashion a INFLUENCED BY RESISTANCE
large collection of genes, each conferring resistance to a MECHANISMS
Resistance of bacteria to antibiotics can result from a vari- As far as therapy is concerned, the most impor- ety of phenomena. There are various biochemical mecha- tant consequence is that cross-resistance means cross- nisms (detoxification of the drug, alteration of the target selection and co-resistance means co-selection. In other of the drug, impermeability of the bacteria to the antibi- words, the use of any antimicrobial to which the strain is otic8 or bypass, different genetic bases (chromosome, plas- resistant will favor dissemination of resistance not only mids, transposons9 and various ways of emergence (muta- to itself and to the other members of the same class tional event, acquisition of foreign genetic information9 of (cross-resistance) but also to various classes of drugs (in resistance. In addition, these bacterial approaches to resis- case of extended cross-resistance or co-resistance) that tance are not mutually exclusive and often coexist in the are structurally unrelated to the antibiotic that exerts the same prokaryotic host often leading to multiresistance.10 selective pressure. This has obvious implications on the We will consider certain aspects of resistance that are “cycling” of antibiotics, which consists of the rotation of common in bacteria responsible for respiratory diseases drugs in a given ecosystem (ward, hospital, community).
and that should be, ideally, kept in mind prior to therapy.
There are pitfalls in the detection of resistance Bacteria can become multiresistant in two ways: phenotypes that can be expressed at low levels. For ex- cross-resistance or co-resistance. In the phenomenon of ample, resistance can be inducible, (i.e., expressed only cross-resistance, a single biochemical mechanism is re- when the bacterium is in the presence of sub-inhibitory sponsible for resistance of the host bacterium to various concentrations of the inducing antibiotic in the envi- levels of all the members of a class of antibiotics. For ex- ronment).9 Because induction can be a slow process, ample, resistance to fluoroquinolones in Streptococcus rapid techniques of determination of in vitro suscepti- pneumoniae can be secondary to mutations in the targets bility may fail to detect this type of resistance, such as of the drugs, the type II topoisomerases.9 However, glycopeptide resistance in enterococci.16 Alternatively cross-resistance to various antibiotic classes can also be certain mechanisms, in particular efflux, often confer due to a single mechanism, for example drug efflux. The low-level resistance that could have clinical consequences.
substrate specificity of the pumps that export antibiotics Selection of resistant mutants can occur under can be very large and, for example, confer in Pseudomo- therapy. Although macrolides, lincosamides, and strep- nas aeruginosa decreased susceptibility to ␤-lactams, togramins (MLS) are chemically unrelated, a specific aminoglycosides, tetracyclines, chloramphenicol, trimeth- modification in the ribosome can confer high-level re- ropim, sulfonamides, fluoroquinolones, and macrolides, sistance to the three classes of antibiotics. This resis- lincosamides, and streptogramins.11,12 This leads to the tance phenotype, which is due to the fact that the vari- notion of extended cross-resistance (i.e., resistance to ous drugs have overlapping targets on the ribosome, is EVOLUTION OF ANTIMICROBIAL RESISTANCE/GUILLEMOT ET AL
inducible by low concentrations of 14-member (ery- main active as penicillinases but have evolved to become thromycin, roxithromycin, clarithromycin, and often also cephalosporinases (conferring resistance to all ceph- oleandomycin) and 15-member (azithromycin) only, the alosporins but cephamycins, cefoxitin, and cefotetan) or other antibiotics remaining active. However, MLS that resistant to inhibitors of penicillinases (clavulanic acid, are noninducers can select only one-step regulatory mu- sublactam, and tazobactam). Because the structural genes tants that are cross-resistant to the three drug classes, as for the enzymes are most often located on plasmids that has been reported in Staphylococcus spp. and in other are self-transferable by conjugation, the emergence and spread of these enzymes represent an interesting exam- As already mentioned, quinolones act by binding ple of cross-resistance to nearly all ␤-lactams by what to type II topoisomerases, DNA gyrase, and topoiso- could be considered as “infectious mutations.” merase IV, and S. pneumoniae can become resistant by Acinetobacter spp. are opportunistic pathogens alteration of the target but also by efflux of the drugs. In that often colonize and infect patients in intensive care both cases, resistance is secondary to a mutational event: units. Acinetobacter baumannii has been found to be re- a regulatory mutation leading to overexpression of an sponsible for epidemic nosocomial pneumonia, and few efflux pump or a mutation in a structural gene resulting drugs are active because of the number of resistance in a decrease in the affinity of the target for the drugs.18 mechanisms accumulated by the bacteria.23 The high The higher the number of mutations, the higher the rate of treatment failures and deaths caused by Acineto- levels of resistance, and the higher the intrinsic activity bacter infections suggests that for certain bacterial of the drug, the lower the level of resistance. However, pathogens, better be resistant than virulent.
and again in this class of antibiotics, there is clearlycross-resistance between all the drugs belonging to theclass.9 For both MLS and fluoroquinolones, the emer- IMPACT OF RESISTANCE ON
gence of resistance under therapy, although it has been CLINICAL RECOMMENDATIONS
documented, does not represent the major threat. As al- (THE INDIVIDUAL APPROACH)
ready discussed, dissemination of antibiotic resistance in Antimicrobial resistance has clearly stressed the need to S. pneumoniae, like in Staphylococcus aureus, is clonal; in optimize antibiotic therapy in community and hospital other words, a few epidemiologically successful multire- settings. In the community, regardless of whether we are sistant clones have, for yet unknown reasons, dissemi- dealing with bacteria responsible for respiratory, urinary, nated worldwide. Thus the spread of resistance to MLS or sexually transmitted infections, evolution toward re- or fluoroquinolones or, even worse, to both, will be sec- sistance is progressively accompanied by modifications ondary to colonization of patients by already resistant in the therapeutic recommendations for first-line an- clones. This also holds true for strains of enterococci tibiotic therapy. In response to the increased number of and staphylococci that are beginning to become resis- Haemophilus influenzae strains producing ␤-lactamases, tant to the new class of drugs, the oxazilidinones.19,20 guidelines for the treatment of otitis have favored a Repeated cures of antibiotics can lead to the se- combination of aminopenicillin and a ␤-lactamase in- lection of hypermutator strains, in particular of P. aerug- hibitor.24–27 Furthermore, the appearance and, above all, inosa21 and S. aureus in patients suffering from cystic fi- the wide dissemination of penicillinase-producing S. brosis (R. Leclercq, personal communication, 2001).
aureus strains has led to the conclusion that community Bacteria with elevated (up to 1000-fold) mutation rates acquired S. aureus infections can no longer be treated have in certain ecosystems a clear advantage to adapt to the repeated sudden and strong selective pressure ex- Among community acquired pathogens, resistance erted against them by antibiotic therapy. S. aureus clini- to antibiotics has increased.28 However, some commonly cal isolates that are resistant to methicillin, and thus to used antibiotics remain effective. The most worrisome all ␤-lactams, are nearly always resistant to fluoroquino- problem is S. pneumoniae resistance because this species lones. The latter class of drugs is increasingly used, in is the main cause of potentially life-threatening commu- particular for pulmonary infections. One could therefore nity acquired diseases such as meningitis and pneumo- anticipate that because of co-resistance to the two nia. In meningitis, delayed administration of appropriate groups of antibiotics and clonal dissemination of staphy- therapy has been linked to poor outcome.29 Retrospec- lococci, massive use of fluoroquinolones will select for tive studies on pneumococcal meningitis in children30 or strains resistant to both ␤-lactams and fluoroquinolones, in intensive care units31 failed to show that nonsuscepti- in particular in community-acquired infections.
bility to penicillins was associated with a worse outcome.
Extended spectrum ␤-lactamases are predomi- Decreased pneumococcal susceptibility to penicillin G has nantly found in K. pneumoniae, an enterobacterial species led to recommendations to increase the doses of amino- responsible for pulmonary infections. The enzymes are penicillin.32 Nevertheless, use of third generation ceph- point mutants of “old” penicillinases.22 The proteins re- alosporins has been shown to lead to treatment failure in SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 23, NUMBER 5 2002
meningitis caused by S. pneumoniae with MIC ≥ 0.5 into account the pharmacokinetic parameters of the µg/mL.29 For pneumococcal meningitis, increased resis- tance to ␤-lactams has resulted in the recommendation As an example of the latter statement, bacteria of an injectable third-generation cephalosporin (cefo- responsible for infection can be initially susceptible to taxime or ceftriaxone) first-line prescription33 in combi- the antibiotic administered and become resistant during nation with a glycopeptide (vancomycin).34 However, one therapy. In nosocomial infections due to P. aeruginosa can anticipate that if the level of resistance to penicillins susceptible to ciprofloxacin, it has been shown that an continues to rise, it could render ␤-lactams even in com- AUC :MIC ratio ≤ 110 can be significantly associated bination with glycopeptides increasingly less effective, with the emergence of ciprofloxacin resistance.40 Thus, resulting in deterioration of the prognosis of pneumo- high dosages of fluoroquinolones have been recommended coccal meningitis by delay in active therapy. This under- to avoid resistance in P. aeruginosa infection. Doses assur- lines the need to continue to update recommendations ing tissue concentrations well above the mutant selection window are, along with drug combinations, strategies used The situation is very different in the field of hos- to restrict development of resistance during therapy.
pital-acquired infections. In many circumstances, only To date, even though the impact of antibiotic very few antimicrobial agents remain effective in partic- treatment on the commensal flora has been widely doc- ular against methicillin-resistant S. aureus or multidrug umented41 how that impact can influence on individual resistant gram-negative bacteria. Although several stud- therapeutic remains currently questionable.
ies have failed to show that nosocomial infections due toantibiotic-resistant bacteria are associated with higherattributable mortality rates than infections caused by IMPACT OF RESISTANCE ON ANTIBIOTIC
their susceptible counterparts, other studies have shown USE POLICIES (THE COLLECTIVE
that administration of inadequate initial antimicrobial APPROACH)
therapy is associated with adverse outcome in critically The impact of bacterial resistance on selection of the ill patients35,36 or after intraabdominal surgery.35,37 In antibiotics to be used may also be analyzed from a pub- these studies the poorer outcome was mainly related to lic health point of view. This automatically raises the inadequate initial antimicrobial therapy due to antibi- question of the existence of a collective regulatory otic-resistant gram-positive or -negative bacteria. Fur- mechanism between the progression of this resistance in thermore, prior antibiotic use or prior use of broad spec- bacteria responsible for infections and the prescription trum antibiotics have been shown to be associated with of antibiotics. In other words, the problem is to deter- ventilator-associated pneumonia caused by antibiotic mine whether the continued expansion of bacterial re- sistance could spontaneously lead to a modification in In bone and joint infections however, methicillin- antibiotic prescription practices and, if so, whether this resistant S. aureus (MRSA) could have a significant im- change itself can, in turn, have an impact on resistance.
pact on the management or the outcome of infections.
As discussed above, the progression of resistance in Direct exchange arthroplasty is not recommended in in- pathogenic bacteria to commercialized antibiotics has fections due to MRSA because of a significant number regularly led to the modification of therapeutic recom- of failures.38 In poststernotomy mediastinitis, MRSA mendations, both in hospitals and in the community.
has been observed as the only independent risk factor The evolution of treatment guidelines has pri- for overall mortality.39 Glycopeptides, in monotherapy marily and naturally been characterized by the preoccu- or in combination, are used as first-line therapy for pation with encouraging the prescription of antibiotics prosthethic and poststernotomy infections because the to which the bacteria are still susceptible; that is to say, vast majority of MRSA remains sensitive to these an- the use of ever more recent molecules. Emergence and tibiotics. Even though glycopeptides remain the refer- spread of resistance to newer antibiotics is the result of ence therapy for MRSA infection, these drugs may not this approach as illustrated by what has been observed be optimal because they are slowly bactericidal. Thus, the poorer prognosis of MRSA infection could reflect This evolution is logical because the basic goal of the long time it takes the molecule to diffuse in bone.
the prescriber is to preserve the individual’s clinical ben- Taken together, these observations underline the efit of the therapeutic intervention. Encouraging changes need (1) to avoid unnecessary use of antimicrobials, es- in antibiotic use with the objective of mastering bacter- pecially broad spectrum antibiotics in hospitalized pa- ial resistance presupposes (1) decreasing the amount of tients, (2) to establish local guidelines taking into ac- prescribed antibiotics by restricting their use to true count local epidemiology and resistance patterns, (3) to bacterial infections, (2) optimizing their use based on develop rapid tests to detect resistance in order to opti- their pharmacokinetic and pharmacodynamic charac- mize the efficacy of the initial therapy and spare the use teristics, (i.e., by adapting dose and duration), (3) avoid- of broad spectrum antibiotics, and (4) to accurately take ing unuseful antibiotic administration.
EVOLUTION OF ANTIMICROBIAL RESISTANCE/GUILLEMOT ET AL
Figure 1 The logic of maximizing only clinical efficacy.
The Physician Level
timicrobial resistance requires both infection control At the hospital setting, use of antibiotics has been measures and regulation of antibiotic use and that either shown to be one of the main risk factors for coloniza- alone is insufficient.72 This leads to close collaboration tion by resistant bacteria and thus for infections due to among the disciplines of infectious diseases, microbiol- resistant organisms.42 Therefore, it is essential to dimin- ogy, hospital epidemiology, pharmacy, and nursing with ish these potential risk factors. Several studies covering strong support from hospital leadership. One can expect antibiotic policies at the hospital have shown that re- that such a dynamic will soon result in an effective pro- stricting the use of antimicrobials can alter prescribers’ gram that can be readily incorporated into the quality- behavior.43–48 These studies also suggest that such a pol- improvement goals of any health care organization.72 icy can have an impact on bacterial resistance.45,49–53 In the community and in many countries, viral res- Strategies aimed at optimizing antibiotic prescription piratory infections represent the main cause for prescrib- are generally based on the use of order forms,54 of guide- ing antibiotics73,74 and medical and scientific leaders have lines, feedback to prescribers or next-day review of voiced their concern that antibiotics are not justified in antibiotic appropriateness,55,56 automatic stop-order 72 this clinical context. Several epidemiological studies have hours after empiric prescription, rotating or combina- shown that it is possible to reduce antibiotic prescription tion therapies,57–60 and computer-based order entry.61–68 in the community.49,75,76 However, in countries with high Thus, restricting the use of antimicrobial agents, pro- community use of antibiotics, there is no evidence of any viding locally adapted guidelines for the prudent use of significant decline in the amount of these drugs, and antibiotics, and implementing quality control of antimi- countries in which antibiotics are not widely prescribed crobial therapy within a hospital, in particular within have generally been low antibiotic users in the past.
the intensive care unit, might help to minimize the se- Thus, the question, Why do general practitioners lection of multidrug-resistant bacteria.69 A recent study overprescribe antibiotics? remains relevant. The most often demonstrated that preapproval of selected parenteral cited reasons for the “resistance” of prescribers to decrease agents reduced the rates of antimicrobial-resistant their use of antibiotics are the expectations of patients; pathogens without compromising patients’ outcome.46 physicians often cite parents’ and patients’ pressure as fac- Monitoring programs based on such axes are currently tors in their decisions to prescribe antibiotics for viral spreading in hospitals.70 Hospital health care workers upper respiratory tract infections.77,78 Although physicians are particulary concerned by bacterial resistance.71 They are sometimes unable to evaluate patients’ expectations ac- daily experiment bacterial resistance as a consequence of curately,78 this may be one of the factors that limits the de- inappropriate use of antibiotics. Therefore, such hospi- crease of antibiotic use in the community, especially in tal mobilization may result from the concern of hospital urban areas where greater numbers of physicians must physicians to both maximize the individual efficacy of compete for patients. Another factor could be related to their antibiotic prescriptions and minime the collective the physician’s perception of bacterial resistance. Although spead of bacterial resistance. Hospital physicians are be- bacterial resistance to antibiotics is an iatrogenic drug coming convinced that addressing the problem of an- problem, the consequences are not yet obvious to the pre- SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 23, NUMBER 5 2002
scribers. It is unlikely that private practitioners can associ- an impact on chronic morbidity and even mortality. As ate their antibiotic prescriptions with infectious complica- previously discussed, this necessitates decreases in the tions in their patients that are due to bacterial resistance exposure to antibiotics and the amounts of prescrip- arising in their patients.Therapeutic failures attributable to tions, which is to say, the volumes sold. At the same bacterial resistance probably remain too uncommon to be time, maximal clinical efficacy must be guaranteed; the perceived by prescribers. In addition, selection of resistant collective therapeutic efficacy of the management of bacteria within the pharyngeal, digestive, or cutaneous bacterial pathologies should not diminish. These objec- flora constitutes the most potent mechanism leading to the tives should probably take into consideration two con- progression of resistance, but this is not tangible to the straints: (1) in developed countries, the guarantee of physician nor to the patient. In the community, physicians minimal public health safety is the responsibility of the do not appear to be concerned by bacterial resistance. The national government, and (2) the sales pressure exerted combined effect of patients’ pressure, lack of perception of by the pharmaceutical industry constitutes a potent force bacterial resistance, and the powerful image of the “new” to increase the volume of drugs used.79 Henceforth, one antibiotics may lead prescribers to use them outside the of the solutions could be that negotiations between the realm of strict recommendations. For example, the “broad pharmaceutical industry, health care providers, and spectrum” qualification, which has been widely used for the the health insurance industry take into consideration most-prescribed ␤-lactams in the community, may have the public health dimension of the potential consequences contributed to an excess in their use outside the target pop- ulation, thus to an increase in human exposure to antibi-otics and the resulting spread of new resistance mecha-nisms (Fig. 2). Henceforth, new solutions are needed.
CONCLUSION
Despite evidence that antimicrobial exposure of the
human population is the most important factor for the
The Level of Public Health Organization
permanent increase in bacterial resistance, the impact of If the progression of bacterial resistance is not con- the latter on antibiotic use has during the past focused trolled, there is a short- or middle-term risk for an in- mainly on clinical efficacy of individual treatment rather crease in therapeutic failures, both in community ac- than on collective control of resistance. It is striking to quired infections such as bacterial otitis in children, note the paradox between the driving force of the evolu- sexually transmitted diseases, or urinary tract infections tion of bacterial resistance and the main modifications and in nosocomial infections. This rise will probably have of precription practices. This underlies the difficulties Figure 2 The example of evolution of Staphylococcus aureus toward multiresistance to antibiotics.
EVOLUTION OF ANTIMICROBIAL RESISTANCE/GUILLEMOT ET AL
for practitioners to take into account the public health 22. Sougakoff W, Goussard S, Gerbaud G, Courvalin P. Plasmid- mediated resistance to third-generation cephalosporins causedby point-mutations in TEM-type penicillinase genes. Rev In-fect Dis 1988;10:879–884 23. Bergogne-Bérézin E, Towner KJ. Acinetobacter spp. as noso- REFERENCES
comial pathogens: microbiological, clinical, and epidemiolog-ical features. Clin Microbiol Rev 1996;9:148–165 1. Bruning LM. Emerging infectious diseases: threats to the 24. Magit AE, Stool SE. Clinical guideline development for oti- OR? Interview by Kimberly Howell. Todays Surg Nurse tis media: a report on methodology. Otolaryngol Head Neck 2. The cost of antibiotic resistance: effect of resistance among 25. Managing otitis media with effusion in young children.
Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter bau- American Academy of Pediatrics, The Otitis Media Guide- mannii, and Pseudomonas aeruginosa on length of hospital stay.
Infect Control Hosp Epidemiol 2002;23:106–108 26. Managing otitis media with effusion in young children. Otitis 3. Carmeli Y, Troillet N, Karchmer AW, Samore MH. Health Media Guideline Panel. Am Fam Physician 1994;50:1003– and economic outcomes of antibiotic resistance in Pseudomo- nas aeruginosa. Arch Intern Med 1999;159:1127–1132 27. Otitis media with effusion in young children: guideline 4. Phelps CE. Bug/drug resistance: sometimes less is more. Med overview. Agency for Health Care Policy and Research, Rockville, Maryland. J Natl Med Assoc 1994;86:731–732, 5. Neu HC. The crisis in antibiotic resistance. Science 1992; 28. Goossens H, Sprenger MJ. Community acquired infections 6. Greenwood D. Preserving the miracle of antibiotics. Lancet and bacterial resistance. BMJ 1998;317:654–657 29. Lebel MH, McCracken GH Jr. Delayed cerebrospinal fluid 7. Lipsitch M. Measuring and interpreting associations between sterilization and adverse outcome of bacterial meningitis in antibiotic use and penicillin resistance in Streptococcus pneu- infants and children. Pediatrics 1989;83:161–167 moniae. Clin Infect Dis 2001;32:1044–1054 30. Buckingham SC, McCullers JA, Lujan-Zilbermann J, Knapp 8. Quintiliani R Jr, Sahm D, Courvalin P. Mechanisms of resis- KM, Orman KL, English BK. Pneumococcal meningitis in tance to antimicrobial agents. In: Murray PR, Jo Baron E, children: relationship of antibiotic resistance to clinical charac- Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical teristics and outcomes. Pediatr Infect Dis J 2001;20:837–843 Microbiology. 7th ed. Washington, DC: American Society 31. Auburtin M, Porcher R, Bruneel F, et al. Pneumococcal meningitis in the intensive care unit: prognostic factors of 9. Courvalin P, Trieu-Cuot P. Minimizing potential resistance: clinical outcome in a series of 80 cases. Am J Respir Crit Care the molecular view. Clin Infect Dis 2001;33(suppl 3):S138– 32. Guillemot D, Carbon C, Balkau B, et al. Low dosage and 10. Courvalin P. Combinatorial approach of bacteria to antibiotic long treatment duration of beta-lactam: risk factors for car- resistance. Res Microbiol 1999;150:367–373 riage of penicillin-resistant Streptococcus pneumoniae. JAMA 11. Paulsen IT, Brown MH, Skurray RA. Proton-dependent mul- tidrug efflux systems. FEMS Microbiol. Rev 1996;60:575–608 33. Tan TQ, Schutze GE, Mason EO Jr, Kaplan SL. Antibiotic 12. Nikaido H. Multidrug efflux pumps of gram-negative bacte- therapy and acute outcome of meningitis due to Streptococcus pneumoniae considered intermediately susceptible to broad- 13. Chiou CC, McEllistrem MC. Novel penicillin-, cephalosporin-, spectrum cephalosporins. Antimicrob Agents Chemother and macrolide-resistant clones of Streptococcus pneumoniae sero- types 23F and 19F in Taiwan which differ from international 34. Rockowitz J, Tunkel AR. Bacterial meningitis: practical epidemic clones. J Clin Microbiol 2001;39:1144–1147 guidelines for management. Drugs 1995;50:838–853 14. Rowe-Magnus DA, Mazel D. Resistance gene capture. Curr 35. Kollef MH, Sherman G, Ward S, Fraser VJ. Inadequate an- timicrobial treatment of infections: a risk factor for hospital 15. Hall RM. Mobile gene cassettes and integrons: moving an- mortality among critically ill patients. Chest 1999;115:462–474 tibiotic resistance genes in gram-negative bacteria. Ciba 36. Kollef MH. Inadequate antimicrobial treatment: an impor- tant determinant of outcome for hospitalized patients. Clin 16. Arthur M, Reynolds P, Courvalin P. Glycopeptide resistance in enterococci. Trends Microbiol 1996;4:401–407 37. Montravers P, Gauzit R, Muller C, Marmuse JP, Fichelle A, 17. Leclercq R, Courvalin P. Bacterial resistance to macrolide, Desmonts JM. Emergence of antibiotic-resistant bacteria in lincosamide and streptogramin antibiotics by target modifica- cases of peritonitis after intraabdominal surgery affects the ef- tion. Antimicrob Agents Chemother 1991;35:1267–1272 ficacy of empirical antimicrobial therapy. Clin Infect Dis 18. Hooper DC. Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis 2001;32(suppl 1):S9–S15 38. Hanssen AD, Osmon DR. Assessment of patient selection 19. Gonzales RD, Schreckenberger PC, Graham MB, Kelkar S, criteria for treatment of the infected hip arthroplasty. Clin DenBesten K, Quinn JP. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001;357:1179 39. Mekontso-Dessap A, Kirsch M, Brun-Buisson C, Loisance D.
20. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance Poststernotomy mediastinitis due to Staphylococcus aureus: com- in a clinical isolate of Staphylococcus aureus. Lancet 2001;358: parison of methicillin-resistant and methicillin-susceptible 21. Oliver A, Canton R, Campo P, Baquero F, Blasquez J. High 40. Hyatt JM, Schentag JJ. Pharmacodynamic modeling of risk frequency of hypermutable Pseudomonas aeruginosa in cystic factors for ciprofloxacin resistance in Pseudomonas aeruginosa.
fibrosis lung infection. Science 2000;288:1251–1253 Infect Control Hosp Epidemiol 2000;21(suppl):S9–S11 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 23, NUMBER 5 2002
41. Sullivan A. Effect of antimicrobial agents on the ecological 60. Labarca J. Antibiotic cycling tested in nosocomial infections.
balance of human flora. Lancet Infect Dis 2001;1:101–114 42. Patterson JE. Antibiotic utilization: is there an effect on an- 61. Evans RS, Burke JP, Classen DC, et al. Computerized identi- timicrobial resistance? Chest 2001;119(suppl):S426–S430 fication of patients at high risk for hospital-acquired infec- 43. Woodward RS, Medoff G, Smith MD, Gray JL III. Antibi- otic cost savings from formulary restrictions and physician 62. Evans RS, Pestotnik SL, Classen DC, Burke JP. Development monitoring in a medical-school-affiliated hospital. Am J Med of an automated antibiotic consultant. MD Comput 1993; 44. Rahal JJ, Urban C, Horn D, et al. Class restriction of 63. Evans RS, Classen DC, Pestotnik SL, Lundsgaarde HP, cephalosporin use to control total cephalosporin resistance in Burke JP. Improving empiric antibiotic selection using com- nosocomial Klebsiella. JAMA 1998;280:1233–1237 puter decision support. Arch Intern Med 1994;154:878–884 45. White AC Jr, Atmar RL, Wilson J, Cate TR, Stager CE, 64. Evans RS, Pestotnik SL. Applications of medical informatics Greenberg SB. Effects of requiring prior authorization for se- in antibiotic therapy. Adv Exp Med Biol 1994;349:87–96 lected antimicrobials: expenditures, susceptibilities, and clini- 65. Evans RS, Classen DC, Pestotnik SL, Clemmer TP, Weaver cal outcomes. Clin Infect Dis 1997;25:230–239 LK, Burke JP. A decision support tool for antibiotic therapy.
46. Richardson LP, Wiseman SW, Malani PN, Lyons MJ, Kauff- Proc Annu Symp Comput Appl Med Care 1995:651–655 man CA. Effectiveness of a vancomycin restriction policy in 66. Evans RS, Pestotnik SL, Classen DC, et al. A computer- changing the prescribing patterns of house staff. Microb assisted management program for antibiotics and other anti- infective agents. N Engl J Med 1998;338:232–238 47. Leverstein-van Hall MA, Fluit AC, Blok HE, et al. Control 67. Hospital antibiotic control measures in the UK. Working of nosocomial multiresistant Enterobacteriaceae using a tem- Party of the British Society for Antimicrobial Chemotherapy.
porary restrictive antibiotic agent policy. Eur J Clin Microbiol 68. Shojania KG, Yokoe D, Platt R, Fiskio J, Ma’luf N, Bates 48. Yates RR. New intervention strategies for reducing antibiotic DW. Reducing vancomycin use utilizing a computer guide- resistance. Chest 1999;115(suppl):S24–S27 line: results of a randomized controlled trial. J Am Med In- 49. Patterson JE, Hardin TC, Kelly CA, Garcia RC, Jorgensen JH. Association of antibiotic utilization measures and control 69. Wester C, Durairaj L, Schwartz D, Husain S, Martinez E, of multiple-drug resistance in Klebsiella pneumoniae. Infect Evans A. Antibiotic resistance who cares? Physician percep- tions of antibiotic resistance among inpatients: its magnitude, 50. May AK, Melton SM, McGwin G, Cross JM, Moser SA, causes, and potential solution [abstract 529]. In: Annual Rue LW. Reduction of vancomycin-resistant enterococcal in- Meeting of the Infectious Diseases Society of America. Phil- fections by limitation of broad-spectrum cephalosporin use adelphia: Infectious Diseases Society of America; 1999 in a trauma and burn intensive care unit. Shock 2000;14:259– 70. Murthy R. Implementation of strategies to control antimicro- bial resistance. Chest 2001;119(suppl):S405–S411 51. Bassetti M, Di Biagio A, Rebesco B, Amalfitano ME, Topal 71. Thrasher CM, Stefl ME, Dorner FH. Antibiotic therapy in- J, Bassetti D. The effect of formulary restriction in the use of tervention at a community hospital: opportunities for cost antibiotics in an Italian hospital. Eur J Clin Pharmacol 2001; and quality improvements. Hosp Top 1995;73:12–15 72. Finkelstein JA, Metlay JP, Davis RL, Rifas-Shiman SL, 52. McGowan JE Jr. Do intensive hospital antibiotic control pro- Dowell SF, Platt R. Antimicrobial use in defined populations grams prevent the spread of antibiotic resistance? Infect Con- of infants and young children. Arch Pediatr Adolesc Med 53. Durbin WA Jr, Lapidas B, Goldmann DA. Improved antibi- 73. Guillemot D, Maison P, Carbon C, et al. Trends in antimicro- otic usage following introduction of a novel prescription sys- bial drug use in the community—France, 1981–1992. J Infect 54. Kortas K, Segreti J, Donnelly A, Pierpaoli P, Trenholme G, 74. Nyquist AC, Gonzales R, Steiner JF, Sande MA. Antibiotic Levin G. An anti-infective review and monitoring program.
prescribing for children with colds, upper respiratory tract in- fections, and bronchitis. JAMA 1998;279:875–877 55. Thuong M, Shortgen F, Zazempa V, Girou E, Soussy CJ, Brun- 75. Zwar N, Wolk J, Gordon J, Sanson-Fisher R, Kehoe L. Influ- Buisson C. Appropriate use of restricted antimicrobial agents in encing antibiotic prescribing in general practice: a trial of pre- hospitals: the importance of empirical therapy and assisted re- scriber feedback and management guidelines. Fam Pract evaluation. J Antimicrob Chemother 2000;46:501–508 56. Shlaes DM, Gerding DN, John JF Jr, et al. Society for 76. Finkelstein JA, Davis RL, Dowell SF, et al. Reducing antibi- Healthcare Epidemiology of America and Infectious Dis- otic use in children: a randomized trial in 12 practices. Pedi- eases Society of America Joint Committee on the Prevention of Antimicrobial Resistance: guidelines for the prevention of 77. Butler CC, Rollnick S, Kinnersley P, Jones A, Stott N. Re- antimicrobial resistance in hospitals. Infect Control Hosp ducing antibiotics for respiratory tract symptoms in primary care: consolidating “why” and considering “how.” Br J Gen 57. Burke JP, Pestotnik SL. Antibiotic cycling: what goes around comes around. Curr Opin Infect Dis 2000;13:367–369 78. Butler CC, Rollnick S, Pill R, Maggs-Rapport F, Stott N.
58. Kollef MH. Is there a role for antibiotic cycling in the inten- Understanding the culture of prescribing: qualitative study of sive care unit? Crit Care Med 2001;29:N135–142 general practitioners’ and patients’ perceptions of antibiotics 59. Evans RS, Pestotnik SL, Burke JP, Gardner RM, Larsen RA, Classen DC. Reducing the duration of prophylactic antibiotic 79. Monnet DL, Sorensen TL. The patient, their doctor, the reg- use through computer monitoring of surgical patients. DICP ulator and the profit maker: conflicts and possible solutions.

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