Activity of Telithromycin against Penicillin-Resistant Streptococcus pneumoniae Isolates Recovered from French Children with Invasive and Noninvasive Infections

Abstract

We compared the activities of telithromycin, erythromycin, azithromycin, josamycin, penicillin G, amoxicillin, cefpodoxime, and ceftriaxone against invasive and noninvasive non-penicillin-susceptible Streptococcus pneumoniae isolates recovered from children. Of the 186 isolates tested, 89% were positive for erm(B) by PCR. Telithromycin had the lowest MICs, with MICs at which 90% of the isolates tested are inhibited of 0.032 and 0.25 μg/ml for erythromycin-sensitive and -resistant isolates, respectively.

Streptococcus pneumoniae is the most common cause of acute otitis media, sinusitis, pneumonia, and bacteremia in children. The worldwide spread of drug-resistant strains of S. pneumoniae has complicated the treatment of these infections and increased the likelihood of treatment failure (2). In the United States, the rates of penicillin resistance in isolates obtained from children are higher than those from adults (25). Penicillin-resistant pneumococci are also particularly frequent in children in France (8-10, 14). Resistance to non-beta-lactam antibiotics, such as macrolides, in pediatric S. pneumoniae isolates has been reported and is often associated with decreased susceptibility to penicillin (2). However, the mechanisms of S. pneumoniae resistance to macrolides differ markedly in isolates from North America and Europe (23).

Since fluoroquinolones are contraindicated in children, few oral treatments are available for respiratory tract infections due to resistant strains. Ketolides are oral semisynthetic derivatives of erythromycin A with enhanced activity against S. pneumoniae (3, 4, 31), but additional susceptibility data are needed to guide empirical treatment. S. pneumoniae susceptibility to telithromycin has been examined in several adult and pediatric studies (7, 16, 20, 24, 27, 31, 34), but there is little data on strains isolated from European children. Therefore, we compared the in vitro efficacies of telithromycin and other antibiotics used in children against well-characterized non-penicillin-susceptible S. pneumoniae strains isolated from French children with invasive and noninvasive infections.

We studied 93 non-penicillin-susceptible S. pneumoniae isolates recovered from children (0 to 15 years old; mostly with pneumonia) by blood culture throughout France and 93 non-penicillin-susceptible S. pneumoniae isolates recovered by tympanic paracentesis from children (less than 2 years old) in the Paris area. Serogrouping was based on coagglutination with antiserum-coated latex particles (10). The MICs of erythromycin, azithromycin, josamycin, telithromycin, penicillin G, amoxicillin, cefpodoxime, and ceftriaxone were determined by the agar dilution method, using Mueller-Hinton medium supplemented with 5% sheep blood and incubation in room air at 35°C (6, 27). S. pneumoniae ATCC 49619 and Staphylococcus aureus ATCC 29213 were used as control strains to ensure that the results were within acceptable quality control limits of the National Committee for Clinical Laboratory Standards (NCCLS) microdilution method (29). The isolates were screened for the mef(A) and erm(B) genes by PCR amplification, as previously described (12, 22, 33).

MIC ranges, MICs at which 50% of the isolates tested are inhibited (MIC₅₀s), and MIC₉₀s are shown in Table 1. Of the 186 non-penicillin-susceptible S. pneumoniae isolates, 105 (56%) were penicillin intermediate (MIC between 0.1 and 1 μg/ml) and 81 (44%) were penicillin resistant (MIC > 1 μg/ml). According to NCCLS breakpoints (30), 4, 79, and 1% of strains were not susceptible to amoxicillin, cefpodoxime, and ceftriaxone, respectively. Both penicillin G and amoxicillin MICs were at least 4 μg/ml for six isolates. Eighty-nine percent of isolates were resistant to erythromycin and azithromycin according to NCCLS breakpoints (30). Overall, the isolates displayed high-level resistance to erythromycin and related agents (Table 1). Eighty-nine percent of isolates were positive for erm(B) by PCR. None of the isolates was mef(A)-positive. Two erm(B)-negative isolates had erythromycin MICs of 0.5 and 1 μg/ml. Neither 23S rRNA mutations nor ribosomal protein mutations were investigated in our work. Telithromycin had the lowest MIC₉₀s (0.25 μg/ml) of the antibiotics tested. The telithromycin MICs ranged from ≤0.008 to 0.064 μg/ml for erythromycin-susceptible isolates (MIC₉₀, 0.032 μg/ml) and from ≤0.008 to 2 μg/ml for erythromycin-resistant isolates (MIC₉₀, 0.25 μg/ml) (Table 2). The serogroups were 19 (27%), 6 (24.5%), 14 (19.5%), 23 (18.5%), 9 (5.5%), 24 (2.5%), 15 (1.5%), and 12 (0.5%).

TABLE 1.

In vitro activities of eight antimicrobial agents against 186 S. pneumoniae isolates

Antibiotic	MIC (μg/ml)a
	Range	50%	90%
Penicillin G	0.125-4	1	2
Amoxicillin	≤0.032-8	1	2
Ceftriaxone	≤0.032-2	0.5	1
Cefpodoxime	≤0.032-16	2	2
Erythromycin	0.016->128	8	>128
Azithromycin	0.064->128	>128	>128
Josamycin	0.032->128	8	>128
Telithromycin	≤0.008-2	0.032	0.25

^a50% and 90%, MICs at which 50 and 90% of isolates are inhibited, respectively.

TABLE 2.

In vitro activities of macrolides and telithromycin against 186 S. pneumoniae isolates according to genetic resistance factors

Isolate and antibiotic	MIC (μg/ml)a
	Range	50%	90%
erm(B) and mef(A) negative isolates (n = 21)
Erythromycin	0.016-1	0.032	0.125
Azithromycin	0.064-4	0.064	0.5
Josamycin	0.125-0.5	0.125	0.25
Telithromycin	≤0.008-0.064	0.016	0.032
erm(B) positive and mef(A) negative isolates (n = 165)
Erythromycin	1->128	64	>128
Azithromycin	1->128	>128	>128
Josamycin	0.5->128	32	>128
Telithromycin	≤0.008-2	0.064	0.25

^a50% and 90%, MICs at which 50 and 90% of isolates are inhibited, respectively.

Recent studies have shown that about 60% of pediatric S. pneumoniae isolates in France have diminished susceptibility to penicillin (9, 10, 14). Resistance to penicillin is frequently associated with pediatric serogroups. Our results show a high rate of erythromycin resistance among pediatric non-penicillin-susceptible S. pneumoniae. In our panel of French strains, erythromycin resistance was associated only with the erm(B) gene, in keeping with previous findings (1, 12, 23). This could be due to clonal spread (9) or to horizontal transfer, as erm(B) is located on a transposon (23). Our study revealed a higher incidence of erm(B) in France than in other countries (11, 20, 23, 27). The spread of such strains limits treatment options for pediatric pneumococcal infections.

Several studies have determined the prevalence of telithromycin susceptibility, but there is little data on highly penicillin-and erythromycin-resistant pediatric isolates of S. pneumoniae. In our study, telithromycin displayed significant activity (MIC₉₀, 0.25 μg/ml) regardless of the presence of erm(B). Telithromycin MICs are generally lower for erm(B)-positive isolates than for mef(A)-positive isolates (20). More than 94% of our isolates were inhibited by 0.5 μg of telithromycin per ml, a clinically achievable level in serum (28). Serum drug levels exceeding the MIC for at least 50% of the dosing interval have been associated with high bacterial cure rates in respiratory tract infections (5, 19). In our study, amoxicillin was the only other oral antibiotic with an MIC₉₀ below the pharmacokinetic breakpoint predictive of bacteriological success (19). The most frequent causative agents of bacterial pneumonia in children aged 5 to 15 years are Mycoplasma pneumoniae and Chlamydia pneumoniae, both of which are beta-lactam resistant and macrolide sensitive. Thus, macrolides have been recommended for the oral treatment of community-acquired pneumonia in this age group (26). However, radiographic and clinical findings often fail to distinguish between cases due to these organisms and cases due to pneumococci (26). Macrolide resistance among pneumococci has been linked to clinical treatment failure in bacteremic pneumonia (13, 17). Thus, in settings of high-level resistance of S. pneumoniae to penicillin and macrolides, the use of telithromycin would increase the chances of effective first-line treatment of respiratory tract infections. Moreover, the bactericidal activity of telithromycin against S. pneumoniae (31) might prevent the risk of secondary sites of infection in bacteremic patients (18, 21, 32). Continuous close surveillance of telithromycin susceptibility is warranted in situations of intensive antibiotic prescription (15).