antibiotic consumption and resistance selection in streptococcus

Journal of Antimicrobial Chemotherapy (2002) 50, Suppl. S2, 27–37DOI: 10.1093/jac/dkf504

27. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

© 2002 The British Society for Antimicrobial Chemotherapy

Antibiotic consumption and resistance selection in Streptococcus pneumoniae

Fernando Baquero1*, Gregorio Baquero-Artigao2, Rafael Cantón1 and César García-Rey3

1Department of Microbiology, Hospital Ramón y Cajal, Carretera de Colmenar Viejo, km 9.1, 28034 Madrid; 2Microbial Sciences Foundation, 28024 Madrid; 3Medical Department, GlaxoSmithKline, Tres Cantos,

Madrid, Spain

Selection of antibiotic-resistant Streptococcus pneumoniae is an inescapable consequenceof antibiotic use. The correlation between antibiotic consumption and selection of resistantorganisms can be shown at every ecological level: patient, community, region or country. In thecase of multiple resistance, the intensity of antibiotic selection is increased. However, differentantibiotics may exert different selective powers. Because of this, co-selection of macrolide andβ-lactam resistance is an asymmetrical phenomenon: macrolides select more efficiently strainsresistant to both macrolides and β-lactams than aminopenicillins. The difference in rates of anti-biotic resistance is also influenced by the local spread of susceptible or resistant clones; it issuggested that under mild antibiotic selection, the susceptible organisms that are more fit forhost-to-host transmission could be favoured. Subsequent acquisition of resistance in theseclones may rapidly increase the prevalence of resistance, and that may lead to an increase in theuse of antibiotics. The reasons for antibiotic resistance are mainly the reasons explaining antibi-otic consumption. A number of possible sociobiological determinants of antibiotic consump-tion can be identified: genetic factors in the human populations (for instance, involving differentsymptomatic types of infection), cultural factors and attitudes of patients towards antibiotics,sociological factors or public health factors, including incidence of other infectious diseases inthe human population. Only ‘excess’ in the use of antibiotics should be controlled; for such apurpose, the concept, ‘appropriate demand for antibiotics’ (ADA) is proposed.

Introduction

If antibiotics are active against microorganisms, and there is adiversity of bacterial phenotypes with respect to the suscepti-bility of bacteria to the antibiotic, selection of the moreresistant among these phenotypes is an inescapable practicalconsequence of antibiotic consumption. Only inactive agentsdo not select for resistance. In recent years a number of papershave discussed the possibility of using antibacterial agentsat sufficient dosage over sufficient time to eradicate in thehost even the bacterial populations with resistant phenotypes(which are not resistant to such intensive exposure to thedrug). This approach, when applied to Streptococcus pneumo-niae, is limited to a number of antibiotics (for instance, someβ-lactams such as amoxicillin), but not applicable to otherssuch as macrolides (since the limitations in the pharmaco-kinetics of these drugs mean that they will never succeed in

reaching the eradication level of exposure for resistant organ-isms). Forced increase in doses or time of exposure makes theapplication of such a strategy to drugs with dose-related lim-ited tolerability somewhat doubtful. In such cases, selectionof resistant populations will occur.

We could succeed in eradicating resistant organisms(minimizing selection) in accurately treated, well supervisedindividual patients. Nevertheless, we should not forget thatselective effects of antibiotics on bacterial populations arecomplex, because the biological, sociological and culturalbackground greatly influences the interface between antibi-otic exposure and bacteria. Indeed, the selection pressureexerted by antibiotics differs greatly between countries,regions, groups and types of patient. Theoretically, educationof prescribers and patients should reduce these differences,but we should not expect such education to have an identicaleffect in different cultural settings.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

*Corresponding author. Tel: +34-91-336-8330; Fax: +34-91-358-0614; E-mail: [email protected]

Downloaded from https://academic.oup.com/jac/article-abstract/50/suppl_3/27/2473461by gueston 02 April 2018

F. Baquero et al.

28

In addition to bacterial factors (prevalence of antibiotic-susceptible and -resistant strains of S. pneumoniae), bothhuman genetic and cultural factors interact to influencethe emergence, spread and control of antibiotic resistance.Clearly, the total amount of antibiotics (either in total numberof grams or number of prescriptions) used per capita differsbetween countries, even considering only the ‘developed’ones. Recent publications have highlighted the differencesexisting in European countries,1 with a clear north–southgradient of antibiotic consumption, and this gradient alsoapplies to antibiotic resistance in bacterial pathogens preval-ent in the community, as in S. pneumoniae. In most countries,resistance to macrolides and β-lactam antibiotics dominatesthe current resistance problems, and we will review in thismanuscript some of the factors that underpin such problems.

Antibiotic use and antibiotic resistance: the ecological links

A correlation between antibiotic use and bacterial resistancehas been demonstrated repeatedly. In the case of S. pneumo-niae, links between antibiotic use and resistance have beenconsistently found at every ecological level: in patients,2

small human communities (for instance day-care centres, seelater), different geographical areas of the same country,3

nationally4 and internationally.5,6 Figures 1 and 2 reflect theessential coincidence of patterns of use and consumption. Toconstruct these figures, different patterns have been applied tocountries with one or two standard deviations above or belowthe average rates of use and consumption. Clearly, there is inboth cases a north–south split in use and resistance.

A very elegant way of determining the relative responsi-bilities of the expansion of resistant clones and the selectiveintensity of the antibiotics in a given environment is tocompare the ability of antibiotics to select resistance simul-taneously in more than a single bacterial species. Thisapproach was applied recently in comparing the 1 yearregional prevalence of macrolide resistance in Streptococcuspyogenes and S. pneumoniae in Spain. A positive correlationwas found in site-by-site comparisons, clearly suggesting thelink with local antibiotic consumption.7 Theoretically thistype of parallel resistance response in different species,i.e. ‘the resistance syndrome’, may also occur because ofthe trans-species transfer of genetic determinants encodingresistance. Nevertheless, in the case of S. pyogenes andS. pneumoniae, macrolide resistance determinants frequentlydiffer [high prevalence of erm(TR) and erm(B), respectively],whereas they may explain parallel increases of resistance inS. pyogenes and Peptostreptococcus spp.8

It should be noted that when comparing rates of resistanceand rates of consumption we should not necessarily expect aparallelism in the resulting curves. The application of the

principles of population genetics to the study of antibioticresistance indicates that there is probably a critical level ofdrug consumption required to trigger the emergence of resist-ance at significant levels. At present, it is unclear whetherthere is a threshold of antibiotic exposure that must be reachedbefore resistance increases within the community, what thethreshold is for the different antibiotics, and whether thisthreshold varies between countries. Moreover, a sigmoid risein resistance over time may be the result of a constant rate ofantibiotic consumption.9 Conversely, resistance rates may notclearly decrease in the short or medium term even when anti-biotic consumption has been significantly reduced. As boththe current use of drugs and the prevalence of resistance arehistorical phenomena (localities with high levels of use orresistance during a period of time also tend to have high levelsduring the next period), it has been suggested recently that thebest correlation might be obtained by considering not theprevalence of antibiotic resistance in a given pathogen, butthe rate of change.10 For the same reasons, the time seriesmethodology of analysis of the correlation between use andresistance is becoming a promising research tool.11

Structure of the selective landscape for antibiotic resistance

Not all classes of antibiotics are equally selective for drug-resistant S. pneumoniae populations. Even within a well-defined group of antibiotics, some members may exert adifferent selective power from others on particular resistantvariants. This phenomenon is a consequence of the differentmechanisms of action, and of the efficiency of bacterial mech-anisms of resistance. It should be noted that the pharmaco-kinetics and pharmacodynamics of the drugs may imbuedifferent antibiotics with different selective qualities.12

Eradication potency of antibiotics

Different antibiotics have quite different eradication powerfor S. pneumoniae. Reduction in the number of oropharyngealcarriers after conventional therapy ranges in different studiesbetween 48% and 80% for co-amoxiclav (conventionaldosage), 22% and 53% for cefuroxime, 41% and 45% for cef-podoxime, 12% and 18% for cefixime, and 14% and 17% forcefaclor.13 The eradication of susceptible organisms, togetherwith the absence of total eradication of the resistant variants,will lead to resistance selection. Because of this, antibioticsshould be able to eradicate both the susceptible target organ-isms (to prevent recurrences) and the resistant variants thatmay be present as part of the population(s) harboured in thepatient (to prevent replacement of the susceptible populationsby the resistant ones). Note that both phenomena are linked:increases in antibiotic resistance reduce the probability of


Antibiotic consumption and resistance selection in S. pneumoniae

29

achieving eradication, and failure to eradicate bacteria maypromote the emergence and dissemination of antimicrobial-resistant clones.14

Low dosages and long duration of treatments with manyβ-lactam drugs increase the risk of selection (and also

increase the rate of carriage) of penicillin-resistant S. pneu-moniae.15 This effect was predicted by in vitro experiments,showing that low concentrations of penicillins selected low-level resistance more efficiently than high-level resistancein mixed cultures with predominance of low-level resistant

Figure 1. (a) Consumption of broad-spectrum penicillins in 1997 (standard deviation, defined daily doses/1000 inhabitants/day). Source: Cars et al.1

(b) Penicillin non-susceptible pneumococci in 2000 (standard deviation). Source: European Resistance Surveillance (EARSS) database; Alexanderproject data; PROTEKT resistance surveillance.


F. Baquero et al.

30

variants.16 In contrast, short-course, high-dose amoxicillintherapy reduces pneumococcal carriage and minimizes theimpact of therapy on the spread of drug-resistant pneumo-cocci.17

In some cases, increased dosages or improved galenicformulations ensuring optimal lengths of contact of the antibi-otic with the target bacterium may be able to eradicate bothsusceptible and resistant populations.18–20 In that case we

Figure 2. (a) Consumption of macrolides in 1997 (standard deviation, defined daily doses/1000 inhabitants/day). Source: Cars et al.1 (b) S. pneumoniaeerythromycin resistance in 2000 (standard deviation). Source: European Resistance Surveillance (EARSS) database; Alexander project data;PROTEKT resistance surveillance.



31

could have an apparently paradoxical effect of antibiotic con-sumption: low dosages (low consumption) may eventuallyselect more resistance than high consumption.21

Despite their bacteriostatic mechanism of action, macro-lides are excellent eradicator agents for macrolide-susceptiblepneumococci. Conversely (and in contrast to the behaviour ofsome penicillins), when used on macrolide-resistant organ-isms, macrolides have an eradication power similar to that ofplacebo.22

Co-selection of macrolide and β-lactam resistance: an asymmetrical phenomenon

Not only the amount, but also the usage of the differentfamilies of antibiotics differs between individual countries.As pneumococcal clones with different blends of antimicro-bial resistance determinants may invade different geograph-ical areas, selection will depend on the interaction of theconsumption of multiple antibiotics and the multi-resistantorganisms. For instance, in many countries S. pneumoniaeclones are simultaneously resistant to β-lactams and mac-rolides. In Spain, there was a strong correlation between theprevalence of high-level penicillin resistance and that oferythromycin resistance (r = 0.903).4 The use of macrolideswill select for both macrolide resistance and β-lactam resist-ance. This has been documented in countries colonized withβ-lactam/macrolide-resistant strains.13

We should therefore expect the converse to be true:β-lactams should act as selectors of macrolide resistance.However, it has been shown that the respective co-selectionby macrolides and penicillins cannot be represented as asymmetrical phenomenon. Multivariate models heve shownthat, in relative terms, in Spain, a country where co-resistanceto β-lactams and macrolides is extremely frequent, at equallevels of consumption, macrolides were almost five-foldmore likely to select for erythromycin resistance, and three-fold more likely to do so for penicillin resistance, than wereβ-lactams.3 In other words, macrolides efficiently select forstrains with erythromycin resistance, including those witherythromycin and penicillin resistance. Penicillins (typicallyhigh-dosage amoxicillin) select less efficiently for penicillin-resistant strains (as a proportion of organisms are inhibited),including strains resistant to both penicillin and erythro-mycin. That means that in a population in which double-resistant strains are frequent, and where the use of amoxicillinis prevalent, there is a possibility of finding a proportion oferythromycin-susceptible clones, but not if the use of mac-rolides is prevalent. Obviously, maximal strength of selectionwill occur if both types of antibiotic (even more if the use oforal cephalosporins is prevalent) are intensively used, as isthe case in France or Spain. Interestingly, differences in theability to select resistant populations can be found amongdifferent members of the same family of antibiotics.

Differences in selective power of different β-lactams and macrolides

In vitro modelling studies have been performed by challeng-ing mixtures of S. pneumoniae strains with different levels ofpenicillin susceptibilities (MICs 0.015, 0.5, 1 and 2 mg/L)with different concentrations of β-lactam agents. Amoxicillinwas a poor selector for the strains with higher MICs incomparison with oral cephalosporins, particularly cefix-ime.22 Indeed, co-amoxiclav reduced nasopharyngeal carriageof penicillin-susceptible S. pneumoniae by 90%, and ofpenicillin-resistant strains by ∼60%. In contrast, cefiximeshowed a reduction of only 30% of penicillin-susceptible iso-lates, without any impact on the carriage of resistant strains.23

Confirming these observations, ecological studies based ondata recovered in the Alexander Project have also suggestedthat a decrease in the prescription ratio of aminopenicillinscompared with cephalosporins per 1000 habitants could becorrelated with the increase in penicillin resistance inFrance.24 Totally consistent results for the higher selectivevalue of oral cephalosporins were obtained by sequentialin vitro selection.25 In addition, we showed in an ecologicalstudy in Spain that the prevalence of high-level penicillinresistance correlated with consumption of oral cephalo-sporins (adjusted r2 = 0.877).4 The reasons for such differencesare related mainly to the effect of different pharmacokineticsof these drugs on susceptible and resistant pneumococcalpopulations.26

Among macrolide agents, an ecological study showed thatthe relationship between erythromycin resistance and mac-rolide consumption was probably due mainly to consumptionof long-acting macrolides (adjusted r2 = 0.886) rather than tothe consumption of erythromycin.4 This is probably due to thelong periods of exposure of bacterial populations to selectiveconcentrations of antibiotics for resistant organisms.4,27 Con-firming these findings, a recent study showed that once-a-daymacrolides are 50% more prone than other macrolides tocause erythromycin resistance at a given site.3

Clonal dynamics and antibiotic resistance

The clonal dissemination of certain resistant S. pneumoniaeorganisms is essential in understanding local resistance rates.For instance, an epidemic strain harbouring mechanisms ofantibiotic resistance may invade a geographical area forreasons unrelated to selection of resistance. In that case, an‘antibiotic resistance epidemic’ may occur in total independ-ence of antibiotic consumption. Conversely, epidemics mayoccur involving clones susceptible to different antibioticgroups. If that were the case, we should expect more suscepti-bility in the invaded regions. The probability of developing(or acquiring) antibiotic resistance seems not to be equivalentamong the different pneumococcal clones. Because of this, itis fully conceivable that in some regions resistance could


F. Baquero et al.

32

remain low despite substantial increases in antibiotic use.Only occasionally, if a resistant clone arrives in this region,would the selective activity of antibiotics (selecting the cloneagainst the susceptible indigenous clones) be fully exerted,and resistance rates might increase rapidly. The naturalhistory of the emergence and spread of pneumococcal resist-ance in different countries mimics a sigmoid growth curve. Apossible cryptic phase is followed by an emergence phase,and once a threshold of prevalence of resistance is crossed, arapid (log-like) penetration phase tends to occur, followedfinally by a stationary phase.28 Mathematical modellingaccounts for these dynamics.9

Under a high antibiotic intensity of selection in a humanpopulation, it is possible that variants of susceptible (or low-level resistant) bacteria that are particularly fit for host-to-host transmission have a higher probability of survival(moving to non-treated hosts). If resistance develops amongthese hyper-transmissible variants (as an effect of its growingdensity in the population), we would expect a rapid penetra-tion of resistance. When the intensity of the antibiotic effecton the bacterial clone decreases (as it is resistant), featuresensuring hyper-transmissibility may no longer constitute anadvantage in comparison with better colonizing abilities ineach particular host. The current lack of animal models for thestudy of in vivo transmissibility of S. pneumoniae makes itdifficult to prove (or disprove) this hypothesis. Perhaps thisapproach should be tested with other streptococci able tocolonize laboratory animals, eventually harbouring (select-able) resistance determinants from S. pneumoniae.

Studies on the population biology (clonal structure) ofS. pneumoniae may help to explain the discrepancies betweenresistance rates in different regions of a wide geographicalarea. Indeed, at national level, comparison of means andvariances of resistance among regions or towns (or hospitalswithin a town) may be useful to describe the phenomenon,and understand the possible discrepancies with antibioticconsumption. In that respect, the possibility of creating mapsof ‘selective environments’ at national or sub-national level(even at hospitals) for particular dangerous (resistant) clonescould be of great interest.

Sociobiological determinants of antibiotic consumption

The reasons for antibiotic resistance are mainly the reasonsthat explain antibiotic consumption. It is essential to investi-gate the reasons that may explain the huge local and country-to-country differences in antibiotic consumption.1 Very fewstudies have been conducted to document the determinants ofantibiotic consumption. Many factors have been suggested toinfluence antibiotic consumption, some of which are listedbelow.

Genetic factors

Genetic factors may influence the host susceptibility toinfectious diseases.29 The bacteria–host relationship has beenrefined during millions of years of co-evolution and the subtlespecificity arising from these interactions could be deter-mined by the host, resulting in different infection-responsepatterns in different populations. For instance, northern humanpopulations may have evolved a less symptomatic responseto infection (for instance, involving weaker induction ofbiological response modifiers), which could influence thepersonal demand for antibiotics. Eventually these popula-tions, to compensate for the obvious environmental risks(such as very cold and humid winters) for respiratory tractinfections (RTIs), could have developed certain types ofmucosal immunity, decreasing the ability of certain bacterialpopulations to produce heavy colonization. Less dense bac-terial populations will decrease the possibility of emergenceof antibiotic resistance. It may be hard to test these hypo-theses, as the sociological environment (for instance, crowd-ing in winter in igloos in Alaska) may provide confoundingfactors.30

The years to come should add important data on theinfluence of host genetics on colonization, transmission andinfection by microorganisms. For instance, some humanpopulations could be more genetically prone than others toharbour and disseminate particular S. pneumoniae clones (seelater). It is a well-known fact that the prevalence of resistanceis strongly influenced by the local spread of a relatively lownumber of resistant bacterial clones. Herd immunity, decreas-ing the dissemination of a resistant clone in a particular geo-graphical area, will certainly influence the resistance rates of agiven pathogen. In general, genetic diversification in humanpopulations will decrease the spread of a given bacterialclone, but at the same time may increase the risk of import-ation of foreign clones. To what extent both the immigrationof resistance and the stabilization plateau of resistant S. pneu-moniae in different countries are influenced by the localgenetic structure of the host populations remains to be investi-gated.

Pharmacogenomic studies may show that human popula-tions can also differ in their ability to absorb, distribute,metabolize and excrete antibiotics. By affecting the pharmaco-kinetics of antibiotics, these differences may also influencethe emergence and selection of antibiotic-resistant micro-organisms. It is interesting to note that European populationsspeaking Germanic languages have lower antibiotic consump-tion and less antibiotic resistance than populations speakingMediterranean or Ugro-Altaic languages, and there is aknown correlation between genetic and linguistic diversity. Itshould be noted that antibiotic resistance is not only the effect,but also an essential cause, of consumption of antibiotics(resistant organisms require higher dosages to be controlled,or the use of alternative antibiotics).



33

Cultural factors and attitudes

Cultural factors and attitudes of patients among differenthuman populations may also contribute to the relationshipbetween tolerance of infective symptoms, severity of symp-toms and antibiotic use, thereby affecting resistance rates.This is reflected by significantly higher community antibioticconsumption, and pneumococcal resistance rates, in southernEurope. For example, the level of symptom severity at whichantibiotic therapy is demanded may be lower in southernEuropean populations than in northern European populations.Psychological tolerance to symptoms versus ask-for-helpattitudes may be influenced by culture and tradition. As a wayof considering the psychological influence of long historicalpatterns of education (for instance, priming self-responsibil-ity in looking for help versus confidence in the group) werecently indicated that antibiotic consumption in countrieswith predominantly Protestant populations is consistentlylower than in those with predominantly Catholic populations.This suggestion has been illustrated recently by DominiqueMonnet (ESAC Meeting, Brussels 2001). Protestant countrieshave a mean consumption of antibiotics near to 13 defineddaily doses (DDDs)/1000 inhabitants/day, and this figure isdoubled in countries of Catholic majority, this differencebeing statistically significant. A frequent patient perception insouthern European countries is: ‘A similar (mild) infection(or any other illness) to that I am now suffering from was suc-cessfully treated on a previous occasion with a particulardrug. As I have such a drug stored at home, I will start with it,or try to get more of it at the pharmacy, or ask my doctor for it.’Such an attitude is the result of public awareness of antibiot-ics—perceived as a cure for infections, often available over-the-counter (OTC), unlike for example angiotensin II antago-nists. Patients frequently stop self-medication (and even pre-scribed drugs) when they feel better, unused antibiotics beingkept for the next episode. Domestic antibiotic pollution hasbeen clearly demonstrated in some surveys. Telephone inter-views with 1000 households in Spain showed that in 42% ofthe homes, one (88.1%) or more antibiotic packets werepresent (80% of these were the remainder of a prescription).31

Economic pressures also play a role, particularly when bothparents are working. The parent will have to take time offwork, certainly if children with infection are not allowed inday-care centres until the episode resolves.

Sociological factors

Sociological factors also play a role in the spread of resist-ance. For example, the proportion of children within thepopulation and the frequency of day-care centre use bothinfluence the prevalence of resistance in the community. Theproportion of oropharyngeal carriers of S. pneumoniaereaches a maximum (∼50–60%) at 1–2 years of age, a figure

that decreases by 50% when children are 8–10 years old.32 Anumber of recent papers have highlighted the role of day-care centres in the transmission of S. pneumoniae local resist-ant clones among children.33,34 Elderly residential care popu-lations are also important, as they may spread hospital-acquired resistant pathogens. Variation in family structures,and differences between urban and rural populations, are alsoimportant. In view of these social influences, policies on anti-biotic usage must be tailored for individual countries.

Epidemiological factors

To understand prescribing practices, it is important to con-sider how the epidemiology of viral RTIs, as well as bacterialRTIs, and even other types of infection, drives antibioticusage. In a study performed in Spain, a country with highlevels of antibiotic consumption and bacterial resistance, theuse of β-lactam and macrolide antibiotics during the years1995–1997 correlates faithfully with the incidence of casesdiagnosed as influenza-like illness.35 The use of quinoloneantimicrobial agents, not used in RTIs, did not show sucha correlation. In support of this observation, DominiqueMonnet36 recently presented data suggesting that countriesdeclaring in 1997 widespread or regional influenza-like ill-ness, as did France and Spain, were much higher consumers ofantibiotics than countries with no activity, such as Denmarkor the Netherlands. It seems probable that a number of febrileviral diseases are treated with antibiotics, particularly amongolder people, on a ‘preventive’ basis; at the same time, viralrespiratory tract diseases may contribute to the spread in thepopulation of resistant bacterial organisms. It is interestingthat children suffering from rhinopharyngitis are more fre-quently carriers of S. pneumoniae.30 The selective landscapemay change with the introduction and wide dissemination ofpneumococcal conjugate vaccines. In a recent 2 year follow-up study, it has been shown that the rate of carriage of vaccine-type pneumococci was lower among toddlers attendingday-care centres who had received a nine-valent conjugatevaccine than among control subjects. The effect is due to alower acquisition rate in the vaccinated group.37

Even the frequency of non-RTIs with cross-therapy withRTIs could be considered as a driver of resistance, forinstance, the use of aminopenicillins and macrolides tocontrol Helicobacter pylori in peptic ulcer, the use of‘respiratory’ fluoroquinolones for UTIs or the use of mac-rolides to prevent the presumed Chlamydia pneumoniaeinfections that are supposed to play a role in coronary arterydiseases. The future wide application of new, effective, safeand non-expensive drugs for respiratory viral diseases couldrepresent a major contribution to reducing the consumption ofantibiotics and perhaps the long-term decrease in antimicro-bial resistance.


F. Baquero et al.

34

Culture and perceptions among community prescribers and suppliers

Many prescribers in community practice do not fully appreci-ate the rationale for restricting the use of antibiotics. Owing tothe self-limiting nature of many community-acquired RTIs,and the fact that antibiotics can often eradicate RTI patho-gens, even those that are defined as ‘resistant’ by standardin vitro testing, prescribers may not directly experience treat-ment failure attributable to bacterial resistance. Spontaneousimprovement or resolution tends to be attributed to medicalintervention (prescription). On the other hand, many prescrib-ers have a preventive feeling: their antibiotic prescription mayhave prevented complications of the RTIs or meningitis (andany possibly associated legal challenge), or may have contrib-uted to the eradication of some important diseases (rheumaticfever). These attitudes (defensive medicine) are expected tobe particularly relevant in areas in which the mean time perconsultation is low. It is also clear that prescription isexpected to be proportional to the number of prescribers. Incountries with a free-market health environment, a highnumber of prescribers could produce competition for patients,and therefore more tolerance of the desires expressed bythem. The same is true for the number of suppliers (pharma-cists), particularly in countries with high tolerance to pro-viding OTC pharmaceuticals. Figure 3 illustrates this point.Comparison of this figure with Figures 1 and 2 reveals theinfluence of these factors on the north–south pattern of anti-biotic use and antibiotic resistance.

Appropriate demand for antibiotics (ADA)

It is essential to understand that antibiotics are absolutelyneeded to maintain high health quality in modern societies. Inthe cases in which antibiotics are indicated, the benefitsoutweigh by far the risks, including antibiotic resistance.Because of that, we should propose that only the excessive useof antibiotics constitutes a dangerous practice for publichealth. The question is how to quantify and control thisexcess. In general, we should be able to construct, for eachparticular area and period of time, a theoretical ‘line ofappropriate use of antibiotics’, correlating (in the abscissa)with the number of infections in which antibiotics are indi-cated (there is an expectation about a positive intervention inthe outcome of the infection), and the rate of use of antibiotics.For instance, during epidemics, the use of antibiotics may alsoincrease in a totally justified way. If that increase does notoccur, there may be under-prescription of antibiotics. If anincrease occurs without any associated increase in the numberof cases, other factors unrelated to justified demand are influ-encing the prescription trends, and measures should be takento control them.

The use of the parameter ‘number of infections in whichantibiotics are indicated’ is just an approximation that shouldbe further refined. For instance, the indication for therapyof pneumococcal pneumonia by a macrolide may exist, butthis indication should be modulated by the local prevalenceof macrolide resistance in S. pneumoniae, increasing theexpected failure rate (the indication exists in general, but maybe not in a particular location). The severity of infection(including chronic infections) should also be considered:patients with severe or chronic infections receive (in ajustified way) more antibiotics than do patients with acute,milder infections. It could be useful to build an integratedparameter considering these facts, to better correlate antibi-otic consumption with real justified needs. This parametershould reflect the ADA in a particular time/space frame.

ADA should be defined in a more specific way in relationto: (i) intent-to-treat organism (for instance, S. pneumoniae,eventually, only macrolide-resistant S. pneumoniae). Clearlyin countries with a high prevalence of resistance, highconsumption of a given antibiotic may be justified but not inanother country with a different resistance pattern; (ii) loca-tion of the patient: sub-country locations for community-acquired infections, but also for hospitals, ICUs, elderlyfacilities or day-care centres; (iii) age and gender of thepatients. For instance, in the absence of paediatric DDDs, thecorrelations between use in grams and appropriate consump-tion may be misleading; (iv) type of infection—are we usingantibiotics appropriately in acute otitis media or chronicbronchitis?

The way of representing antibiotic use is certainly a majorissue. The classic methods based on DDDs require furtherEuropean standardization. The main difficulty is the dis-crepancies between countries of antibiotic dosage and lengthof therapy in different types of infection. In some cases, this isdue to differences in antibiotic susceptibilities of frequentpathogens. Perhaps a ‘local correction index’ could be intro-duced to obtain a more faithful representation of the realconsumption. This index could be obtained on the basis ofrealistic prescribed daily doses (PDDs). Cosentino et al.38 havesuggested that DDD/day/ADU (apparent drug users, that is,individuals for whom at least one prescription of the drug hasbeen dispensed during a given time period) = PDD × days.

Correlation studies of antibiotic use and antibiotic resist-ance in particular pathogens can be carried out with each oneof these values representing antibiotic use. For many patho-gens that are members of normal microbiota, we can theor-etically consider the total amount of antibiotics used (grams)in a period of time as a ‘collective prescription’ of a givenselective intensity exerted on a ‘collective microbial flora’.Indeed, the main difficulty of these studies is based on thecurrent international classification of antimicrobial agents in‘families’ (Jn-groups). This classification is most frequentlyused for usage analysis and it is not always helpful to our



35

understanding of the relationship between use and resistance,since these groups are highly heterogeneous in terms ofselective activity for particular mechanisms of resistance.Perhaps, it would be desirable for this particular purpose tobuild new groups of antibiotics with common selective activ-

ities on particular mechanisms or even (why not?) on particu-lar bacterial clones that we are trying to contain.

Clearly, many factors play a role in the development ofantibiotic resistance and the interplay of these factors needs tobe better understood. The key to achieving benefits in terms of

Figure 3. (a) Pharmacists per 1000 inhabitants in 1998 (standard deviation). (b) Over-the-counter pharmaceutical expenditure (last year availablefor all countries; standard deviation). Source (a and b): European Health For All database, WHO Regional Office for Europe, Copenhagen, Denmark.


F. Baquero et al.

36

curing infectious diseases is to be able to assess accurately therisk of antibiotic resistance in populations and then to manageit appropriately. Mathematical modelling may be a way tocondense complex sets of dispersed data and produce mean-ingful predictions able to inspire successful interventions.

Acknowledgements

The authors are greatly indebted to both Lorenzo Aguilar(Medical Department, GlaxoSmithKline Spain) for his scien-tific support to the Consumption/Resistances Programme, andto Gerry Halls for providing data and thoughts during severaldiscussions about antibiotic consumption and resistance.

References

1. Cars, O., Mölstad, S. & Melander, A. (2001). Variation in antibi-otic use in the European Union. Lancet 357, 1851–3.

2. del Castillo, F., Baquero-Artigao, F. & García-Perea, A. (1998).Influence of recent antibiotic therapy on antimicrobial resistance ofStreptococcus pneumoniae in children with acute otitis media inSpain. Pediatric Infectious Disease Journal 17, 94–7.

3. García-Rey, C., Aguilar, L., Baquero, F., Casal, J. & Dal-Ré, R.(2002). Importance of local variations in antibiotic consumption andgeographical differences of erythromycin and penicillin resistance inStreptococcus pneumoniae. Journal of Clinical Microbiology 40,159–64.

4. Granizo, J. J., Aguilar, L., Casal, J., García-Rey, C., Dal-Ré, R.& Baquero, F. (2000). Streptococcus pneumoniae resistance toerythromycin and penicillin in relation to macrolide and β-lactamconsumption in Spain (1979–1997). Journal of Antimicrobial Chem-otherapy 46, 767–73.

5. Felmingham, D. & Grüneberg, R. N. (2000). The AlexanderProject 1996–1997: Latest susceptibility data from this internationalstudy of bacterial pathogens from community-acquired lowerrespiratory tract infections. Journal of Antimicrobial Chemotherapy45, 191–203.

6. Baquero, F., Barrett, J. F., Courvalin, P., Morrisey, I., Piddock,L. & Novick, W. J. (1998). Epidemiology and mechanisms of resist-ance among respiratory tract pathogens. Clinical Microbiology andInfection 4, Suppl. 2, S19–26.

7. Pérez-Trallero, E., Fernández-Mazarrasa, C., García-Rey, C.,Bouza, E., Aguilar, L., García-de-Lomas, J. et al. (2001). Antimicro-bial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039Streptococcus pyogenes isolates and their ecological relationships:Results of a 1-year (1998–1999) multicenter surveillance study inSpain. Antimicrobial Agents and Chemotherapy 45, 3334–40.

8. Reig, M., Galán, J., Baquero, F. & Pérez-Díaz, J. C. (2001).Macrolide resistance in Peptostreptococcus spp. mediated byermTR: possible source of macrolide–lincosamide–streptogramin Bresistance in Streptococcus pyogenes. Antimicrobial Agents andChemotherapy 45, 630–2.

9. Austin, D. J., Kristinsson, K. G. & Anderson, R. M. (1999). Therelationship between the volume of antimicrobial consumption inhuman communities and the frequency of resistance. Proceedingsof the National Academy of Sciences, USA 96, 1152–6.

10. Lipsitch, M. (2001). The rise and fall of antimicrobial resistance.Trends in Microbiology 9, 438–44.

11. López-Lozano, J. M., Monnet, D. L., Yague, A., Burgos, A.,Gonzalo, N., Campillos, P. et al. (2000). Modelling and forecastingantimicrobial resistance and its dynamic relationship to antimicro-bial use: a time series analysis. International Journal of Anti-microbial Agents 14, 21–31.

12. Ball, P., Baquero, F., Cars, O., File, T., Garau, J., Klugman, K.et al. (2002). Antibiotic therapy of community respiratory tract infec-tions: strategies for optimizing outcomes and minimizing resistanceemergence. Journal of Antimicrobial Chemotherapy 49, 31–40.

13. Cohen, R. & Varon, E. (2001). Flore rhinopharyngée: impactdes traitements antibiotiques conventionnels. La Lettre de l’Infectio-logue 16, 12–6.

14. Dagan, R., Klugman, K. P., Craig, W. A. & Baquero, F. (2001).Evidence to support the rationale that bacterial eradication inrespiratory tract infection is an important aim of antimicrobialtherapy. Journal of Antimicrobial Chemotherapy 47, 129–40.

15. Guillemot, D., Carbon, C., Balkau, B., Geslin, P., Lecoeur, H.,Vauzelle-Kervroedan, F. et al. (1998). Low dosage and longtreatment duration of β-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. Journal of the AmericanMedical Association 279, 365–70.

16. Baquero, F., Negri, M. C., Morosini, M. I. & Blázquez, J. (1997).The antibiotic selective process: concentration-specific amplifica-tion of low-level resistant populations. Ciba Foundation Symposium207, 93–111.

17. Schrag, S. J., Pena, C., Fernández, J., Sánchez, J., Gómez, V.,Pérez, E. et al. (2001). Effect of short-course, high-dose amoxicillintherapy on resistant pneumococcal carriage: a randomized trial.Journal of the American Medical Association 286, 49–56.

18. Kaye, C. M., Allen, A., Perry, S., McDonagh, M., Davy, M.,Storm, K. et al. (2001). The clinical pharmacokinetics of a newpharmacokinetically enhanced formulation of amoxicillin/clavulanate.Clinical Therapeutics 23, 578–84.

19. Berry, V., Singley, C., Satterfield, J. & Woodnutt, G. (2001).Efficacy of a pharmacokinetically enhanced formulation of amoxi-cillin/clavulanate against experimental respiratory tract infection(RTI) in rats caused by Streptococcus pneumoniae (Sp.). In Pro-gram and Abstracts of the Forty-first Interscience Conference onAntimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001.Abstract B-988, p. 53. American Society for Microbiology, Washing-ton, DC, USA.

20. File, T., Jacobs, M., Poole, M., Richard, M. & Wynne, B. (2001).Clinical efficacy of pharmacokinetically enhanced amoxicillin/clavulanate (AMX/CA) vs. comparators against Streptococcuspneumoniae (Sp) in respiratory tract infections (RTIs). In Programand Abstracts of the Forty-first Interscience Conference on Antimi-crobial Agents and Chemotherapy, Chicago, IL, USA, 2001.Abstract L-866, p. 451. American Society for Microbiology,Washington, DC, USA.

21. Lipsitch, M. (2001). Measuring and interpreting associationsbetween antibiotics and penicillin resistance in Streptococcuspneumoniae. Clinical Infectious Diseases 32, 1044–54.



37

22. Negri, M. C., Morosini, M. I., Loza, E. & Baquero, F. (1994). Invitro antibiotic selective concentrations of β-lactams for penicillin-resistant Streptococcus pneumoniae populations. AntimicrobialAgents and Chemotherapy 38, 122–5.

23. Dabernat, H., Geslin, P., Megraud, F., Begue, P., Boulesteix, J.,Dubreuil, C. et al. (1998). Effects of cefixime or co-amoxiclav treat-ment on nasopharyngeal carriage of Streptococcus pneumoniaeand Haemophilus influenzae in children with acute otitis media.Journal of Antimicrobial Chemotherapy 41, 253–8.

24. Baquero, F. (1996). Antibiotic resistance of respiratory patho-gens: an analysis and commentary on a collaborative surveillancestudy. Journal of Antimicrobial Chemotherapy 38, Suppl. A, 117–32.

25. Pankuch, G. A., Jueneman, S. A., Davies, T. A., Jacobs, M. R.& Applebaum, P. C. (1998). In vitro selection of resistance to fourβ-lactams and azithromycin in Streptococcus pneumoniae. Antimi-crobial Agents and Chemotherapy 42, 2914–8.

26. Thorburn, C. E., Knott, S. J. & Edwards, D. I. (1998). In vitroactivities of oral β-lactams at concentrations achieved in humansagainst penicillin-susceptible and -resistant pneumococci andpotential to select resistance. Antimicrobial Agents and Chemother-apy 42, 1973–9.

27. Baquero, F. (1999). Evolving resistance patterns of Strepto-coccus pneumoniae: a link with long-acting macrolide consumption?Journal of Chemotherapy 11, Suppl. 1, 35–43.

28. Baquero, F. (1996). Epidemiology and management of penicillin-resistant pneumococci. Current Opinion in Infectious Diseases 9,372–9.

29. Qureshi, S. T., Skamene, E. & Mallo, D. (1999). Comparativegenomics and host resistance against infectious diseases.Emerging Infectious Diseases 5, 36–47.

30. Cohen, R. & Varon, E. (2001). Variations de la flore oro- etrhinopharyngée en dehors des antibiotiques. La Lettre de l’Infectio-logue 7, 4–8.

31. Orero, A., González, J. & Prieto, J. (1997). Antibiotics inSpanish households. Medical and socioeconomical implications.URANO Study Group. Medicina Clínica 109, 782–5.

32. Loda, F. A., Collier, A. M., Glezen, W. P., Strangert, K., Clyde,W. A. & Denny, F. W. (1975). Occurrence of Diplococcus pneumo-niae in the upper respiratory tract of children. Journal of Pediatrics87, 1087–93.

33. Sá-Leao, R., Tomasz, A., Santos-Sanches, I., Nunes, S., Alves,C. R., Brito-Avô, A. et al. (2000). Genetic diversity and clonalpatterns among antibiotic-susceptible and -resistant Streptococcuspneumoniae colonizing children: day care centres as autonomousepidemiological units. Journal of Clinical Microbiology 38, 4137–44.

34. Sá-Leao, R., Tomasz, A., Santos-Sanches, I., Brito-Avô, A.,Vilhelmsson, S. E., Kristinsson, K. G. et al. (2000). Carriage ofinternationally spread clones of Streptococcus pneumoniae withunusual drug resistance patterns in children attending day carecentres in Lisbon, Portugal. Journal of Infectious Diseases 182,1153–60.

35. Moreno, R. (2000). Ph.D. Thesis, School of Medicine, Univer-sidad Complutense de Madrid, Spain.

36. Monnet, D. (2001). European Conference on Antibiotic Con-sumption, ESAC November 2001. http://oms2.b3e.jussieu.fr-/flunet/activity.html

37. Dagan, R., Givon-Lavi, N., Zamir, O., Sikuler-Cohen, M., Guy,L., Janco J. et al. (2002). Reduction of nasopharyngeal carriage ofStreptococcus pneumoniae after administration of a 9-valentpneumococcal conjugate vaccine to toddlers attending day carecentres. Journal of Infectious Diseases 185, 927–36.

38. Cosentino, M., Leoni, O., Banfi, F., Lecchini, S. & Frigo, G.(2000). An approach for the estimation of drug prescribing using thedefined daily dose methodology and drug dispensation data. Euro-pean Journal of Clinical Pharmacology 56, 513–7.


antibiotic consumption and resistance selection in streptococcus

Documents