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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
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Module 6 ~ notes ~ marketing

Module Six is all about marketing. I’m going to share with you my experiences and what I’ve learned from running a thriving business. Nothing is a more powerful marketing tool than knowing who you are. That gives you a sense of confidence that is infectious. Your cake style is basically your business truth. It’s who you are. These days with so many gimmicks, being an open and honest business

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Dres. María Inés Mota, Gustavo Varela, Br. María del Pilar Gadea y colaboradores ARTÍCULOS ORIGINALES Rev Med Uruguay 2005; 21: 30-36 Serotipos, perfil plasmídico y antibiotipos de cepas de Shigella flexneri aisladas de niños menores de 5 años con diarrea sanguinolenta usuarios de los servicios de Salud Pública Dres. María Inés Mota*, Gustavo Varela†, Br. María d

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