Worldwide trends in antimicrobial resistance among common... : The Pediatric Infectious Disease Journal (original) (raw)
INTRODUCTION
Respiratory tract infections among children are a common reason for health care provider visits and the primary reason for antimicrobial prescribing in this population. In the United States alone, there are >50 million office visits annually for respiratory tract infections among children younger than 15 years of age.1 By 6 months of age, 39% of children have had a first episode of acute otitis media (AOM), with 20% developing recurrent AOM.2
Streptococcus pneumoniae and Haemophilus influenzae are the predominant bacterial pathogens in respiratory childhood infections, with Moraxella catarrhalis being at a distant third.3-5 Resistance to antimicrobials among these pathogens has emerged as a worldwide problem in the past 20 years and has escalated in the past decade. This article reviews the problems of antimicrobial resistance among these pathogens, with a focus on surveillance data of respiratory tract isolates obtained from pediatric patients when available.
MECHANISMS OF RESISTANCE
Antibiotic resistance can be either intrinsic or acquired.6 Natural or intrinsic resistance occurs because of inaccessibility of the target (i.e. impermeability resistance caused by the absence of an adequate transporter), multidrug efflux systems or drug inactivation.7 For example, the majority (>98%) of H. influenzae strains have an intrinsic macrolide efflux mechanism that causes these pathogens to be macrolide-resistant.8 Likewise, beta-lactamase-producing H. influenzae may result in reduced susceptibility to some cephalosporins and penicillins, which may be overcome with second and third generation cephalosporins.9
Bacteria may acquire resistance to antimicrobials to which they were previously susceptible through a variety of genetic mechanisms. S. pneumoniae develop resistance to penicillin and other beta-lactam antimicrobials primarily through alterations in penicillin-binding proteins (PBPs), which are vital to the synthesis and maintenance of the bacterial cell wall. Modifications to the cell wall caused by altered PBPs reduce the affinity of the beta-lactam ring for its active PBP site. Although as little as a single amino acid mutation can confer beta-lactam resistance, the most highly penicillin-resistant strains (MIC ≥ 2 μg/ml) have more PBP alterations than strains that exhibit intermediate penicillin resistance (MIC 0.12 to 1 μg/ml).10 Susceptibility of all beta-lactams, including amoxicillin and third generation cephalosporins, decreases with decreasing penicillin susceptibility. However, beta-lactam antimicrobials can maintain efficacy against PBP-mediated resistance if adequate drug concentrations are achieved and maintained at the site of infection for an adequate period of time. In pneumococcal infections, adequate bactericidal activity can be achieved if the unbound serum drug concentration of beta-lactams can be maintained above the MIC of the invading pneumococcus for 40 to 50% of the dosing interval.11
Two genetic acquisitions are responsible for most pneumococcal macrolide resistance. The acquisition of an erythromycin ribosomal methylation (erm) gene results in posttranscriptional modification of 23S ribosomal RNA, blocking the binding of the macrolide to the ribosome. Once expression of the gene is induced, the organism has complete resistance to macrolides, lincosamides and streptogramin B. Pneumococcal _erm_-mediated resistance is often high level (i.e. MICs >128 μg/ml).12, 13 Erythromycin, azithromycin and clarithromycin susceptibilities against pneumococci also are adversely affected by bacterial acquisition of a macrolide efflux system (_mef_E) gene, although MICs are not as high as for strains with the ribosomal methylation resistance mechanism. Expression of _mef_E genes results in pumping of the antimicrobial out of the cell via an efflux system. The efflux pump is not effective against 16-membered macrolides (e.g. roxithromycin), ketolides and lincosamides. In the United States, the efflux system is the predominant form of pneumococcal macrolide resistance, existing in approximately two-thirds of macrolide-resistant strains as compared with one-third of macrolide-resistant strains having the erm gene.14-16 Unlike beta-lactam resistance, pneumococcal resistance to macrolides via these mechanisms is absolute, because the antimicrobial dosage cannot be increased sufficiently to overcome these mechanisms.17
Fluoroquinolone resistance occurs as a result of key mutations in the DNA gyrase or topoisomerase IV enzymes.18 In addition to these genetic mutations, fluoroquinolone resistance can result from expression of efflux mechanisms within bacteria that pump antimicrobial agents out of the cell. Piddock et al.19 reported that an efflux pump contributes to resistance in S. pneumoniae and decreases the activity of moxifloxacin, grepafloxacin, gatifloxacin, trovafloxacin and clinafloxacin. The third mechanism of fluoroquinolone resistance involves altered porins or channels in the cell membrane. These resistance mechanisms have clinical manifestations in fluoroquinolone treatment failures.20-23
The principal mechanism of resistance against penicillins in H. influenzae, M. catarrhalis and many other Gram-positive and Gram-negative bacteria is the production of beta-lactamase. These enzymes hydrolyze the beta-lactam ring, inactivating the antimicrobial. More than 200 beta-lactamases are naturally occurring in bacteria.24 Two approaches have been used to counter beta-lactamase-conferred resistance: the development of beta-lactam antimicrobials resistant to hydrolysis (advanced generation cephalosporins, monobactams and carbapenems); and the combination of beta-lactamase inhibitors (clavulanic acid, tazobactam and sulbactam) with beta-lactam antimicrobials.24 Beta-lactamase-negative, ampicillin-resistant (BLNAR) H. influenzae also have been detected in surveillance studies and appear to be mediated through two specific PBP modifications.25-27
Resistance of H. influenzae and S. pneumoniae to trimethoprim-sulfamethoxazole (TMP-SMX) is directed at the trimethoprim component through overproduction of mutated dihydrofolate reductase.28-30 Dihydrofolate reductase is necessary for the production of bacterial thymidine and amino acids. Sulfonamide resistance in H. influenzae is mediated by 2 distinct mechanisms: acquisition of a resistant dihydropteroate synthase (DHPS) encoded by the plasma-borne gene, sul2, and alteration of the chromosomal gene encoding DHPS, _folP._31-33 Similarly, sulfonamide resistance in other species, including S. pneumoniae and Neisseria meningitidis, is mediated by mutation of the chromosomal gene encoding DHPS.31, 34, 35 Similar to erythromycin, resistance to TMP-SMX is generally absolute and cannot be overcome with appropriate dosing regimens as can be done with some beta-lactams.
Antimicrobial resistance is spread between organisms and to other species by transfer of genetic material. Plasmids are small circular DNA elements that encode for activities of virulence, resistance and genes necessary for mobilization and transmission of plasmid elements.36 Transfer of resistance can be plasmid-mediated, transferring genetic material directly from plasmids to chromosomes by simple recombinational steps, or facilitated by transposons, which are mobile DNA elements that remove and insert themselves into host chromosomal and plasmid DNA.36 Material can also be transferred horizontally or vertically by plasmids, although these pathways are less efficient. Additionally, resistance determinants carried on the chromosome can be transferred directly via vertical clonal dissemination. Transformation, which occurs through direct incorporation of free DNA by bacterial cells, is another mechanism by which organisms such as pneumococci acquire resistance.36, 37
Evidence suggests that the spread of penicillin resistance among pneumococci is primarily the result of aggressive proliferation of relatively few clones of stable, resistant pneumococci that spread via human-to-human transmission. Most S. pneumoniae strains with a reduced susceptibility to penicillin are represented by a limited number of clonal groups.38-40 The emergence of new S. pneumoniae strains with reduced susceptibility to penicillin and genetic and phenotypic differences among strains with similar DNA fingerprinting patterns in recent years suggest that in addition to clonal spread, penicillin resistance is conferred through horizontal transfer of genes encoding altered PBPs, capsule formation genes and other genetic determinants from S. pneumoniae strains with reduced susceptibility to penicillin.38, 40 Recent evidence suggests that dissemination of H. influenzae BLNAR strains occurs through intra- and interhospital transmission of a BLNAR clone.41
Resistance to various classes of antimicrobials occurs as separate events, although all occur in response to antimicrobial selective pressure. The increasing development of S. pneumoniae resistance to the antimicrobials most frequently prescribed for common infections is occurring worldwide, although at different rates.42 The hypothesis that variations in antibiotic consumption contribute to geographic differences in resistance has been evaluated. European studies demonstrate linear correlations between oral cephalosporin and macrolide use and increasing prevalence of S. pneumoniae with reduced susceptibility to penicillin.42-44 In an epidemiologic study conducted in the United States from 1993 to 1999, macrolide consumption increased 13% in the general population and increased 320% in children younger than 5 years of age. During that same time period, macrolide resistance among S. pneumoniae isolates increased from 10.6% in 1995 to 20.4% in 1999.15
Antimicrobial resistance is increasing globally, although patterns and degree of resistance vary by geographic region. National and worldwide surveillance programs have been invaluable in tracking trends in antimicrobial resistance among respiratory tract pathogens. The Alexander Project has provided data on the susceptibility of S. pneumoniae, H. influenzae and M. catarrhalis to antimicrobials in adults since 1992 and included centers in 26 countries between 1998 and 2001.45
S. pneumoniae.S. pneumoniae with reduced susceptibility to penicillin was first noted in the late 1960s. However, little attention was paid to this pathogen until highly resistant strains were reported from South Africa in 1977.46, 47 Although the first US report of S. pneumoniae with reduced susceptibility to penicillin occurred in 1974, it was not until the early 1990s that there was a major increase in its prevalence (Fig. 1).14, 48
Increased trends in reduced penicillin susceptibility among S. pneumoniae clinical isolates in the United States, 1992 to 2000.48-53
From 1998 to 2000, the worldwide prevalence of S. pneumoniae isolates resistant to penicillin (MIC ≥ 2 μg/ml) was 18.2% (Table 1).45 Specifically, penicillin resistance increased significantly in Poland from 2.2% in 1998 to 10.7% in 1999 through 2000 (P = 0.001), in Portugal from 8.8% in 1998 through 1999 to 16.7% in 2000 (P = 0.04) and in South Africa from 7.3% in 1998 to 20.7% in 1999 through 2000 (P = 0.013). Although the incidence of S. pneumoniae with reduced susceptibility to penicillin increased in Spain from 22.3% in 1998 to 37.4% in 1999 (P = 0.016), it decreased to 20.8% in 2000 (P = 0.009). Likewise, the incidence of penicillin resistance increased in the United States from 22.2% in 1998 to 31.0% in 1999 (P < 0.001) but decreased to 22.7% in 2000 (P < 0.001). The United Kingdom has seen a decrease in the incidence of S. pneumoniae with reduced susceptibility to penicillin from 17.6% in 1998 to 7.2% in 1999 through 2000 (P = 0.013).
Worldwide susceptibility of Streptococcus pneumoniae to penicillin with the use of NCCLS breakpoints, 1998 to 2000*
Susceptibilities to other antimicrobials have decreased in tandem with reduced penicillin susceptibility. S. pneumoniae resistance to macrolides (erythromycin MICs ≥1 μg/ml) was 24.6% overall from 1998 to 2000 and exceeded penicillin resistance in 19 of the 26 countries included in the Alexander Project.45 Specifically, macrolide resistance increased significantly in Israel from 9.3% in 1998 to 20.5% in 1999 (P = 0.045), in Mexico from 18.3% in 1999 to 28.9% in 2000 (P = 0.04) and in Spain from 19.4% in 1998 to 28.6% in 1999 through 2000 (P = 0.016). Although the incidence of macrolide resistance in S. pneumoniae increased from 25.1% in 1998 to 34.6% in 1999 (P < 0.001) in the United States, it then decreased significantly to 26.8% in 2000 (P < 0.001). In the SENTRY data set, similar increases were observed with erythromycin resistance in the United States from 1997 through 1998 (from 9.8% to 15.9%) to 1999 (23.7%).54 Significant decreases in S. pneumoniae resistance to macrolides were observed in Switzerland from 19.2% in 1998 to 9.4% in 1999 through 2000 (P = 0.008).45
During the Alexander Project, S. pneumoniae resistance to TMP-SMX was also high from 1998 to 2000, with an overall rate of 24.8%.45 In the United States, it increased from 35.2% in 1998 to 43.4% in 1999 but then decreased to 34.1% in 2000 (P < 0.001).
Although prevalence remains relatively low, fluoroquinolone resistance to S. pneumoniae is an increasing concern because these agents are often used in adults who have failed other treatments, and use of quinolones is likely to be extended into the pediatric population in the future.55 In the Alexander Project, fluoroquinolone nonsusceptibility (ofloxacin MICs ≥ 8 μg/ml) increased from 0.54% in 1997 to 1.1% in 1998 through 2000 (P = 0.01).45, 56 However, the rate of resistance in Hong Kong increased from <0.5% for ofloxacin to 5.5% for levofloxacin (MIC > 2 μg/ml) within 3 years.57, 58 In <2 years, the prevalence of levofloxacin nonsusceptibility has increased from 5.5% to 13.3% among all strains and from 9.3% to 28.4% among S. pneumoniae strains with reduced susceptibility to penicillin.59 Canada has seen a rise in ciprofloxacin-resistant (MIC ≥ 4 μg/ml) S. pneumoniae, from 1.5% to 2.9% between 1993 and 1998.59, 60
Based on National Committee for Clinical Laboratory Standards (NCCLS) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints used in the Alexander Project, amoxicillin (95.1%) and amoxicillin/clavulanate (95.5 to 97.9%) were the only oral nonfluoroquinolone agents active against >90% of S. pneumoniae isolates.45 Of the fluoroquinolones, gemifloxacin was the most active agent (99.9% susceptibility), and ofloxacin was the least active agent (92.7% susceptibility) against S. pneumoniae. The lowest susceptibility was seen for cefaclor, TMP-SMX and cefixime (all <70%).
The highest prevalence of S. pneumoniae with reduced susceptibility to penicillin is most often observed among children. In a 1997 US surveillance study, the proportion of penicillin-nonsusceptible (intermediate or resistant) S. pneumoniae strains was higher among patients younger than 2 years of age compared with patients older than age 2 years (58.3% vs. 42.1%, respectively; P < 0.001).4 The prevalence of penicillin-resistant S. pneumoniae strains from the middle ear was higher than that of penicillin-intermediate strains in patients younger than 2 years of age (49.7% vs. 19.5%, respectively; P < 0.001).
Other US surveillance studies have demonstrated higher rates of S. pneumoniae with reduced susceptibility to penicillin in children than in adults. In isolates obtained from outpatients during the winter of 1994 to 1995, rates of S. pneumoniae with reduced susceptibility to penicillin were 31% among isolates obtained from pediatric facilities compared with 22% for those obtained primarily through adult hospital outpatient clinics (P < 0.005).48 Of isolates obtained from different specimen types, again, the middle ear fluid had the highest prevalence (42.3%) of S. pneumoniae isolates that were either penicillin-intermediate or penicillin-resistant. In surveillance testing of samples obtained during the winter of 1999 to 2000, 42.5% of samples from children had S. pneumoniae with reduced susceptibility to penicillin, which was 7 to 10% higher than the rate in any other age group.14
Similar trends in S. pneumoniae resistance to penicillin in children have been documented worldwide. In middle ear fluid specimens obtained from 917 infants and children with AOM plus effusion in 1997, the rates of S. pneumoniae that were intermediately or fully resistant to penicillin were 21% in the United States, 31% in eastern/central Europe and 52% in Israel.5 In a 1998 to 1999 study in Switzerland, the prevalence of nasopharyngeal penicillin-nonsusceptible S. pneumoniae isolates ranged from 43.9% among infants from birth to 1 year of age to 30.6% among children 2 to 4 years of age and 25.5% among children 5 to 16 years of age.61 In Spain in 2000, a total of 51.7% of S. pneumoniae strains were resistant to penicillin in children 4 years of age or younger, compared with 29% of strains in children older than 4 years (P < 0.001).62 However, in a study conducted in Germany from 2000 to 2001, only 7.5% of S. pneumoniae strains collected from outpatients younger than 16 years of age who had respiratory tract infections were penicillin-intermediate and none was penicillin-resistant.63
The recommendation of administering heptavalent pneumococcal conjugate vaccine (PnCV) to infants and toddlers64 has shown a modest decrease in otitis media of ∼8%.65-68 However, in a study in which children living in a largely unvaccinated population received three doses of heptavalent pneumococcal conjugate vaccine in infancy and 23-valent pneumococcal polysaccharide vaccine at 13 months of age, the effects of vaccination in infancy on rates of pneumococcal nasopharyngeal carriage and serotype replacement are no longer evident by 2 to 5 years of age.69
H. influenzae. As with S. pneumoniae with reduced susceptibility to penicillin, the highest prevalence of beta-lactamase-producing H. influenzae strains is in children.4, 70 In the United States, the proportion of clinical H. influenzae isolates producing beta-lactamase increased from 20% in 1986 to a leveling off at ∼35% in the 1990s and has decreased most recently (Fig. 2).26, 41, 49, 53, 70-74
H. influenzae beta-lactamase production in the United States, 1986 to 2001.26, 41, 49, 53, 70-74
In Canada, H. influenzae beta-lactamase production rates were 32% in 1993 and 1994, 31.3% in 1997 and 24% in 1997 to 1998.75-77 The reported prevalences of beta-lactamase-producing H. influenzae in western Europe increased from 11.6% in 1998 to 19.2% in 1999 through 2000.78, 79 More specifically, strains of beta-lactamase-producing H. influenzae increased significantly in France between 1998 and 1999 through 2000 (20.3% vs. 30.8%, respectively; P = 0.018) but decreased significantly in Spain between 1998 and 1999 through 2000 (28.2% vs. 16.4%; P = 0.014).45 Rates of beta-lactamase production among H. influenzae isolates were 13% from eastern/central Europe and 25% from Israel in the analysis of middle ear fluid specimens obtained from 917 infants and children worldwide.5 Rates of beta-lactamase production among H. influenzae isolates were 15.4% in Japan and 6% in China from 1997 to 1998.80
BLNAR strains are found rarely in Europe and the United States, with an overall prevalence of 0.1 to 0.3%.41, 70, 78 However, in Japan, BLNAR strains are more common. Between 1996 and 1997, pharyngeal samples were collected from children age 12 years or younger with a respiratory infection. From these samples, 74 isolates of H. influenzae were isolated, of which only 14.9% produced beta-lactamase, but 44% of beta-lactamase-negative isolates were BLNAR.81 Although the frequency of beta-lactamase-producing H. influenzae in Japan has not increased since 1980, the incidence of BLNAR in this study was remarkable given earlier reported frequencies in the range of 2 to 5% from 1984 to 1991.81
A multinational surveillance project in adults found that based on NCCLS and PK/PD breakpoints, ceftriaxone, cefixime and high dose amoxicillin/clavulanate were the most active beta-lactams against H. influenzae, all with >99% susceptibility (Table 2).45 Based on PK/PD parameters, cefprozil and cefaclor were the least active oral beta-lactams against H. influenzae. In addition, very few H. influenzae isolates are susceptible to macrolides (≤1.2%) or doxycycline (28.9%) based on PK/PD breakpoints. Resistance to fluoroquinolones was found rarely.
Worldwide susceptibility of Haemophilus influenzae to various antimicrobials and MIC90 values, 1998 to 2000*
M. catarrhalis. Beta-lactamase production is extremely prevalent among M. catarrhalis isolates and has been for some time. Among M. catarrhalis isolates obtained from the middle ear fluid of children worldwide, 100% produced beta-lactamase.4 According to 1998 through 2000 data from a surveillance study in adults, beta-lactamase production of M. catarrhalis worldwide remained at 92.1% during this time period.45 Nonetheless, amoxicillin/clavulanate, cefdinir and cefixime (100%) remain highly active against M. catarrhalis. Cefixime, chloramphenicol, gatifloxacin and moxifloxacin were active against M. catarrhalis; however, cefaclor and cefprozil were the least active against this pathogen (10.9 and 16.0% susceptibility, respectively).
RISK FACTORS FOR INFECTION WITH RESISTANT PATHOGENS
Risk factors for infection with a resistant pathogen have been well-defined and include recent antimicrobial use, young age (<24 months of age), the site of infection (upper respiratory tract, sinus or middle ear have a higher risk compared with blood or lower respiratory tract) and day-care center attendance.3, 82-85 Nasopharyngeal carriage of respiratory bacterial pathogens is often a source of intra- and interpersonal infection. Colonization with pneumococci in healthy individuals was first described in the late 1800s.86 Children facilitate the person-to-person spread of bacterial nasopharyngeal carriage and the likelihood of infection via respiratory secretions/droplets. Worldwide, there is a high prevalence of nasopharyngeal carriage of S. pneumoniae among both healthy and sick children.
Factors associated with nasopharyngeal carriage of resistant S. pneumoniae among children include day-care center attendance, recent antimicrobial use, young age (e.g. preschool), presence of siblings younger than 2 years of age in the household and male gender.87-92 In the United States, white race was found to be an independent risk factor for nasopharyngeal carriage of S. pneumoniae with reduced susceptibility to penicillin.87 One study found that unresolved otitis media was diagnosed more often in children colonized with penicillin-resistant pneumococci than in children colonized with penicillin-susceptible strains (P = 0.04).92
Day-care centers provide an excellent environment for the spread of carriage and infection, because children are often in large groups and in close quarters, and many receive antimicrobial therapy for respiratory tract infections. In a US study, there was no difference in nasopharyngeal pneumococcal carriage rates between urban and rural day-care centers.93 A study of different day-care centers in Israel found that each day-care center has a unique microenvironment with different rates of carriage of pneumococci, resistant pneumococci and serotype distribution.88
Antimicrobial treatment of AOM may select out resistant pneumococci and allow them to flourish in the nasopharynx. Dagan et al.94 evaluated the effects of antimicrobial use on nasopharyngeal carriage during AOM in 120 children, 63% of whom carried pneumococci, of which 43% had reduced susceptibility to penicillin. After 3 to 4 days of treatment with a beta-lactam antimicrobial, susceptible pneumococci were not recovered from the nasopharynx, and most nonsusceptible pneumococci were not eradicated. Among children receiving azithromycin, azithromycin-resistant strains also persisted, and resistant strains were now present in patients initially negative for these strains. The proportion of isolates resistant to at least one antimicrobial increased significantly after 3 to 4 days of antimicrobial treatment, from 47% pretreatment to 74% (P = 0.004). In a study evaluating macrolide resistance of oral flora in children with respiratory tract infections, carriage of resistant bacteria in the oral flora increased significantly with azithromycin treatment, with 85% of children harboring resistant bacteria at the end of the study period.95 In contrast, carriage of resistant bacteria was reduced significantly during clarithromycin treatment, with only 17% of children colonized with resistant isolates.
Worldwide, nasopharyngeal carriage of H. influenzae is also high ("normal flora"). Among children ages 1 month to 5 years with acute respiratory tract infections in China, 36% had nasopharyngeal colonization of _H. influenzae._96 Trimethoprim-sulfamethoxazole resistance among pediatric nasopharyngeal isolates of H. influenzae in China has also increased significantly from 40.5% in 1999 to 77% in 2000, which is one of the highest documented resistance rates in the world. Among Egyptian children 2 to 60 months old hospitalized with pneumonia, 73% carried either S. pneumoniae or H. influenzae in the nasopharynx, and 40% carried both organisms.97
CLINICAL IMPLICATIONS OF RESISTANCE
The major implications of antimicrobial resistance in the treatment of respiratory tract infections are increased treatment failures and increased costs of treatment. Treatment failures and chronic infection appear to be caused mainly by resistant pathogens. During a 15-year period in France, the increasing prevalence of S. pneumoniae with reduced susceptibility to penicillin and beta-lactamase-producing H. influenzae causing persistent AOM has been increasing in children (Table 3).98 Among children in San Diego, CA, undergoing tympanocentesis or endoscopic sinus surgery (i.e. suggestive of chronic problems) in whom S. pneumoniae was isolated from a middle ear fluid or sinus aspirate sample, 58% of isolates had reduced susceptibility to penicillin.85 In children in Denver, CO, with chronic sinusitis for >8 weeks from 1995 to 1998, S. pneumoniae, H. influenzae and M. catarrhalis occurred with similar frequencies (19, 24 and 17%, respectively); rates of nonsusceptibility of S. pneumoniae were 64% for penicillin, 40% for cefotaxime and 18% for clindamycin. Of H. influenzae and M. catarrhalis isolates, 39% and 100%, respectively, produced beta-lactamase.99
Bacteriologic results during a 15-year study period from middle ear fluid specimens in children 3 months to 6 years old with persistent otitis media in France*
To combat the increased spread of resistance, several approaches should be considered. First, antimicrobials should be prescribed only when clinical presentation clearly suggests a high probability of bacteriologic etiology. In programs that focused on reduced regional antimicrobial prescribing among children, the prevalence of S. pneumoniae with reduced susceptibility to penicillin did not increase or decrease, suggesting that judicious prescribing may attenuate the spread of resistance.100, 101 Second, the empiric treatment of respiratory tract pathogens in children should provide coverage for S. pneumoniae with reduced susceptibility to penicillin and beta-lactamase-producing H. influenzae in areas of high resistance. Should coverage for both pathogens be necessary, there are few options for this age group, with amoxicillin/clavulanate being the only oral agent currently available that has activity in >90% of isolates.4 Antimicrobial dosing must be based on PK/PD parameters to ensure optimal bactericidal activity and to limit selective pressure.
Lastly, new antimicrobials that provide enhanced coverage of resistant organisms must continually be developed. New formulations of amoxicillin/clavulanate that improve the bactericidal activity of amoxicillin while retaining the beta-lactamase-inhibitory effects of clavulanate have recently become available. A new high dose formulation of amoxicillin/clavulanate (90/6.4 mg/kg/day) (Augmentin ES-600 Powder for Oral Suspension; GlaxoSmithKline, Research Triangle Park, NC) for use in children has an increased amount of amoxicillin compared with the regular strength amoxicillin/clavulanate (45/6.4 mg/kg/day) formulation. The amount of clavulanate is the same in both formulations. In an open label, multinational, bacteriologic outcome study of 521 infants and children with AOM, many of whom were at risk for infection with a resistant pathogen (i.e. day-care center attendance, previous antimicrobial use and younger than 2 years of age), high dose amoxicillin/clavulanate (90/6.4 mg/kg/day) eradicated infection in 99% of children infected with S. pneumoniae, 91% of children with S. pneumoniae with reduced susceptibility to penicillin (penicillin MICs of 2 to 4 μg/ml), 92% of children infected with H. influenzae, 100% of children infected with M. catarrhalis and 91% of children infected with both S. pneumoniae and _H. influenzae._83 This was a bacteriologic outcome study, with etiology determined by tympanocentesis at screening (i.e. pretherapy) and outcome by repeat tympanocentesis on Days 4 to 6 of therapy. Adverse events were similar to those found with regular strength amoxicillin/clavulanate.
CONCLUSIONS
Despite geographic variations in prevalence, antimicrobial resistance among upper respiratory tract pathogens is a worldwide problem. Isolates obtained from children exhibit the highest degrees of resistance, and all classes of antimicrobials used in this patient population are affected. Worldwide prevalence of S. pneumoniae with reduced susceptibility to penicillin is 18.2%. Beta-lactamase production among H. influenzae ranges from ∼4% in Russia to 26% in the United States and to 31% in France. The differences in prevalence of resistance between some countries despite geographic proximity are reflective of different antimicrobial selection pressures in each country. Risk factors for infection with a resistant pathogen in children include young age, the site of infection, day-care center attendance and recent antimicrobial use.
Measures must be implemented to arrest the spread of resistance worldwide. The importance of judicious antimicrobial prescribing to limit selective pressure cannot be overemphasized. Research into the development of new antimicrobials must be continued aggressively. Clinicians must use local resistance surveillance data to assist in guiding antimicrobial selection, with agent choice and dosing based on optimizing pharmacokinetic and pharmacodynamic parameters in light of resistance.
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**Section Description
This supplement was funded by a grant from GlaxoSmithKline. Editorial support was provided by Scientific Therapeutics Information, Inc., Springfield, NJ.
Keywords:
Antimicrobial; antimicrobial resistance; respiratory tract infection; amoxicillin/clavulanate
© 2003 Lippincott Williams & Wilkins, Inc.