Laboratoire de Microbiologie Médicale, Fondation Hôpital Saint-Joseph, 185 rue Raymond Losserand, 75674 Paris Cédex 14, France
In recent years there has been a dramatic increase, worldwide, in the prevalence of so-called penicillin-resistant Streptococcus pneumoniae (PRSP);1 in some European countries and certain regions of the USA, South America and South East Asia, prevalences currently exceed 4050%. The overall increase has been attributed to excessive global usage of antibiotics, particularly ß-lactams, and, in an attempt to address this problem, it has been proposed that prescribing of these drugs should be reduced or avoided altogether. Clearly such an initiative is impractical in those clinical settings in which ß-lactams are considered essential therapeutic agents. The more realistic strategy continues to be identification of those patients who require antibiotics and prescription of the most active compound at the optimal dosage for the optimal duration. Insofar as it is possible, the drug chosen should also have a low propensity for selecting resistant strains.
PRSP strains may be selected either at the site of infection, where they may lead to clinical failure, or in the nasopharynx, from which they can be disseminated. Resistant strains may be present in the nasopharynx before therapy is initiated and subsequently selected by the antibiotic administered, or they may be acquired during therapy from another carrier, or they may be selected de novo by transformation or mutation. In theory, any antibiotic can select resistant strains, as long as the local concentration of the drug exceeds the MIC for the susceptible bacterial population but is below the MIC for the resistant clone. The risk of selection is enhanced in the presence of low antibiotic concentrations (usually secondary to the administration of low dosages), or when antibiotics with poor in-vitro activities are prescribed, or following prolonged courses of treatment.2 The risk of selecting PRSP is particularly high in patients with pneumococcal infections, in whom both the carriage rate and inocula of pneumococci tend to be high, compared with patients with infections caused by other bacteria, in whom the pneumococcal nasopharyngeal carriage rate and inocula are much lower.
Of the various classes of antibiotics, ß-lactams, and particularly aminopenicillins, are widely regarded as being disproportionately responsible for selecting PRSP,3,4,5,6,7,8,9,10 presumably because the emergence of this pathogen coincided with increased consumption of these antibiotics.7 However, the increase in the prevalence of PRSP can also be shown to coincide with increases in the number of cellular telephones, readers of the Journal of Antimicrobial Chemotherapy and other seemingly unrelated parameters. A more detailed analysis might reveal that increased prescribing of cephalosporins, co-trimoxazole and macrolides are equally or, indeed, more important than aminopenicillins in terms of promoting PRSP carriage.6,7,8,9,10 A mistake that is common to the studies described below, and others, is that the investigators estimated the percentages of PRSP carriage among children harbouring S. pneumoniae on completion of courses of antibiotic treatment; they ought to have calculated the percentages of carriers on the basis of the total numbers of children who were treated with antibiotics, on the grounds that these drugs may inhibit the susceptible commensal flora, thereby suppressing the `barrier effect' of these organisms and facilitating colonization by resistant strains.10
In a study in which the efficacy of cefixime was compared with that of co-amoxiclav in children with acute otitis media, the former drug was associated with a rate of selection of PRSP of 41.9%, compared with 15.9% for the latter.5 The selection of PRSP by oral cephalosporins, both in vitro11 and in vivo,5 can be explained by their reduced activities against PRSP, as well as by the fact that the modification of a single penicillin-binding protein (PBP), PBP 2x, may result in a marked increase in MICs. Selection by cephalosporins occurs at higher frequencies than that by amoxycillin.11 Even very potent broad-spectrum cephalosporins are capable of selecting PRSP. For example, in a study in which a single dose of ceftriaxone was compared with a 10-day course of co-amoxiclav as treatment of patients with acute otitis media who lived in an area of high PRSP prevalence,10 nearly twice as many PRSP were selected by ceftriaxone as by co-amoxiclav in evaluable children (27.4% and 14.5%, respectively). In a second study, previous antibiotic courses (P = 0.0001), white race (P = 0.0002) and administration of ß-lactams (P = 0.03) were shown to be risk factors for PRSP carriage.9 Regrettably, the authors did not calculate the relative selective pressures of oral cephalosporins and aminopenicillins, each of which represented 50% of all ß-lactams administered.
The authors of a further report2 suggested that ß-lactams, and particularly aminopenicillins, were responsible for selecting six of 16 PRSP strains, although they did not specify the antibiotics that selected the remaining 10 (62.5%). It is, therefore, unclear if the PRSP strains were selected by other antibiotics or if they were acquired by other children by cross-infection. In many studies, the investigators failed to identify the specific antibiotics administered, referring only to the generic term `antibiotics'. In one such study, day-care centre attendance, current and previous antibiotic usage and current otitis media were risk factors for PRSP carriage.12 Interestingly, 98.3% and 91.5% of these PRSP were also resistant to co-trimoxazole and erythromycin, respectively. However, information regarding the precise antibiotics the children received is not provided. In another study, carriage of PRSP was associated with refractory otitis media, but not with otitis media in general.13 This study demonstrates the adverse consequences (including clinical failure) of administering antibiotics that allow high densities of pneumococci to persist at the site of infection, thereby enhancing the risk of resistant strains being transmitted to other individuals. Unfortunately, the antibiotics responsible for these consequences were not specified. More puzzling are those studies in which the authors identified the classes of antibiotics that selected resistant strains, but did not complete the analysis. In one of these studies, co-amoxiclav was shown to be associated with a minimal increase in the incidence of PRSP carriage, i.e. from 14% to 16%, compared with the controls, while the use of `other' (unidentified) antibiotics was associated with a much greater increase in the incidence of PRSP carriage, i.e. from 39% to 70%.14
In some studies, the conclusions of the authors are unwarranted. For example, in the frequently cited study of Ford et al.,6 13 PRSP strains were isolated from the middle ear fluid of children who, before the specimens were obtained, had been given a total of six different antibiotic regimens. An unspecified number of children had previously received several (in some cases more than 20) courses of antibiotics; c. 95% received co-trimoxazole and c. 75% co-amoxiclav. The investigators observed that co-amoxiclav was the only antibiotic that was significantly associated with the subsequent isolation of PRSP, i.e. this drug had been used in a significantly higher percentage of children in the group from whom strains of PRSP were isolated and had been administered nearer to the culture date, compared with the group from whom penicillin-susceptible strains were recovered. However, it is impossible to determine which antibiotic(s) selected the resistant strains or at which stage selection occurred. It may have been that the last antibiotic prescribed was given because of the failure of previous agents which had already selected strains of PRSP. Implicating the last drug administered as the cause of selection is inappropriate.
Non-ß-lactam antibiotics are undoubtedly capable of exerting selective pressures. Selection may occur once multidrug-resistant strains of S. pneumoniae, such as those belonging to serotype 6B or 23F, emerge and spread. Indeed, any antibiotic to which a strain is resistant will exert a selective pressurea phenomenon that is well-documented in respect of Staphylococcus aureus and Enterobacteriaceae. Multidrug-resistant strains of S. pneumoniae, which already represent therapeutic challenges, have greater potential to spread than susceptible strains. In an important study performed in Iceland, co-trimoxazole (OR = 13.14) and erythromycin (OR = 12.16) selected twice as many PRSP as ß-lactams (OR = 6) in children who had received three or more courses of treatment.15 Swedish investigators also recently reported that co-trimoxazole was the only antibiotic that was associated with a significantly increased risk of carriage of PRSP (OR = 3.48).16 In another recent study, 29.4% of PRSP were selected by azithromycin, compared with 12.2% by co-amoxiclav.17 Selection of PRSP by macrolides has been documented in France, where these agents have been used for many years as treatment of patients with respiratory tract infections, and in many South-East Asian countries, such as Taiwan, where macrolides are used as first-line antibiotics, accounting for a 98% incidence of resistance to these drugs amongst PRSP isolates.18 A study from Slovakia similarly showed that erythromycin selected twice as many strains of PRSP as ampicillin (OR = 7.9 vs 3.9).19 This phenomenon may also have occurred in South Africa, Hungary and Spain, where more than 20,000 kg of co-trimoxazole were used annually in the late 1970s. The availability of these compounds without prescription in some countries has undoubtedly contributed to excessive and inappropriate antibiotic usage. Finally, the use of co-trimoxazole in patients infected with human immunodeficiency virus has been associated with increased incidences of infection caused by PRSP in this group20,21,22,23,24 and, as early as 1988, Henderson et al.25 reported an increase in the incidence of co-trimoxazole-resistant S. pneumoniae isolates from 0% to 34.4% only 18 months after the introduction of this agent as treatment of otitis media in children; interestingly, resistance to penicillin increased from 0% to 28.1% during the same period.
The susceptibilities to penicillin, erythromycin, chloramphenicol, tetracycline and
co-trimoxazole of 628 strains of S. pneumoniae isolated between January 1997 and June
1998 in the course of several multicentre studies performed in France are summarized in the
Table (Goldstein, F. W., unpublished data). Also shown are the numbers
and percentages of
PRSP that were resistant to the other drugs tested and the numbers and percentages of isolates
resistant to each of these drugs that were also resistant to penicillin. Overall, 54% of the strains
were resistant to penicillin (MICs 0.12 mg/L) and 52.2% to erythromycin (MICs
2
mg/L). Of
the penicillin-resistant strains, 268 (79.1%) were also resistant to erythromycin, compared with
only 19.9% of the penicillin-susceptible strains (data not shown); in France, macrolides are
therefore not suitable alternatives to penicillin as treatment of patients with infections caused by
PRSP. Of the isolates that were resistant to the non-ß-lactam antibiotics tested, the
likelihood of one of these strains also being resistant to penicillin is between 76.5% and 87.9%.
The data in the Table reveal that, in the event of a patient failing to
respond to therapy, the risk of
selecting a penicillin-resistant isolate is markedly higher if the strain is already resistant to a drug
belonging to another class of antibiotics.
|
It is indisputable that aminopenicillins promote the carriage of PRSP. In common with other ß-lactams, they may select PRSP strains already present in the oropharynx or other penicillin-resistant oral streptococci which might serve as reservoirs for resistance genes that encode mutations leading to alterations to the PBPs of pneumococci. However, because of cross-resistance and reduced activities against PRSP, the selective pressures exerted by oral cephalosporins are even greater. Concurrent resistance to other antibiotics, including macrolides and co-trimoxazole, in multidrug-resistant strains will not only select still greater numbers of resistant clones in the nasopharynx, but may also lead to clinical failures, thereby increasing the risk of disseminating PRSP. In a recent report, previous administration of erythromycin plus sulphizoxazole was significantly (P = 0.006) associated with the isolation of PRSP from patients with otitis media who had failed to respond to antibiotic therapy.27
In conclusion, efforts to administer antibiotics that have low propensities for promoting PRSP carriage should take account of the selective pressures not only of ß-lactams, in particular aminopenicillins, but also those of other classes of antibiotics.2,4,6,7,12,13
Acknowledgments
I thank Dr Keith Klugman, Johannesburg, South Africa, for helpful comments and critical reading of the manuscript and Monique Boda for secretarial assistance.
Notes
* Tel: +33-1-44-12-34-53; Fax: +33-1-44-12-32-34.
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