Abstract
The in vitro activities of faropenem and other antimicrobial agents were determined against 4,725 Streptococcus pneumoniae isolates, 2,614 Haemophilus influenzae isolates, and 1,193 Moraxella catarrhalis isolates collected from 273 U.S. laboratories during 1999. Faropenem MICs at which 90% of isolates are inhibited were 0.008, 0.25, and 1 μg/ml for penicillin-susceptible, -intermediate, and -resistant S. pneumoniae strains, respectively; 0.5 and 1 μg/ml for β-lactamase-positive and -negative H. influenzae strains, respectively; and 0.12 and 0.5 μg/ml for β-lactamase-negative and -positive M. catarrhalis strains, respectively. Faropenem holds promise as an oral therapy for community-acquired respiratory tract infections.
The increasing levels of antimicrobial resistance among community-acquired respiratory tract pathogens limit the options for empirical therapy (2). Penicillin resistance among Streptococcus pneumoniae strains is now widely accepted as a global problem (1, 7, 10), and the widespread dissemination of plasmid-encoded β-lactamases in Haemophilus influenzae and Moraxella catarrhalis has eliminated amoxicillin as a treatment option for infections caused by β-lactamase-producing isolates (6). Although penem antimicrobials have broad-spectrum activities, remarkable potencies, and stabilities against β-lactamases, none are available, to date, for oral administration. The parenteral carbapenems imipenem (14) and meropenem (5) are prescribed in the United States, and a number of new oral carbapenems are now in development, including L-084 (11) and DU-6681a (16).
Faropenem is a novel β-lactam antimicrobial with a penem (furanem) structure that is being developed for use as an oral therapy for community-acquired respiratory tract infections. Although recent studies have highlighted the broad-spectrum antibacterial activity of faropenem (previously known as SUN/SY 5555, ALP-201, or WY-49605) (8, 9, 15, 17–19), new attention has focused on its activity against the respiratory pathogens S. pneumoniae, H. influenzae, and M. catarrhalis (3). The aim of the present study was to benchmark the activity of faropenem against recent bacterial pathogens isolated from patients with respiratory tract infections.
Respiratory tract isolates were collected from 273 hospital laboratories distributed throughout the United States during 1999 as part of the LIBRA surveillance program. Isolates were limited to one per patient and were collected from clinical samples derived from various upper and lower respiratory tract sites, blood, ears, and eyes. All isolates were shipped to the central laboratory of Focus Technologies, Inc. (Herndon, Va.), where each isolate was subcultured and reidentified by standard methods (12).
A total of 4,725 isolates of S. pneumoniae were available for antimicrobial susceptibility testing; 58.9% (2,783 isolates) originated from respiratory specimens, 32.1% (1,517 isolates) originated from blood or cerebrospinal fluid, 4.7% (220 isolates) originated from eye specimens, and 4.3% (205 isolates) originated from other or unknown specimen sources. A total of 2,614 isolates of H. influenzae were tested for their susceptibilities to faropenem and imipenem; 2,483 of the 2,614 isolates were tested for their susceptibilities to all other agents. Of the 2,614 isolates, 83.3% (2,177 isolates) originated from respiratory specimens, 10.1% (264 isolates) originated from eye specimens, 3.2% (83 isolates) originated from blood or cerebrospinal fluid, and 3.4% (90 isolates) originated from other or unknown specimen sources. A total of 1,193 isolates M. catarrhalis were available: 91.0% (1,086 isolates) originated from respiratory sources, 4.9% (58 isolates) originated from eye specimens, 1.4% (17 isolates) originated from blood, and 2.7% (32 isolates) originated from other or unknown specimen sources.
The isolates were tested for their susceptibilities to faropenem, ampicillin (H. influenzae and M. catarrhalis only), amoxicillin-clavulanate, ceftriaxone, cefuroxime, imipenem, levofloxacin, penicillin (S. pneumoniae only), and trimethoprim-sulfamethoxazole (SXT) by using antimicrobial concentrations that extended at least 1 twofold concentration above and 1 twofold concentration below the NCCLS breakpoints (where available). Antimicrobial susceptibility testing was conducted by the broth microdilution method with frozen panels prepared by PML Biologicals (Wilsonville, Oreg.) in accordance with NCCLS guidelines. For S. pneumoniae and H. influenzae, breakpoint interpretations were conducted according to the recommendations of NCCLS (13) with the exception of those for faropenem, for which no NCCLS breakpoints are available. In the case of M. catarrhalis, no NCCLS breakpoints were available. H. influenzae and M. catarrhalis isolates were tested for the production of β-lactamase by the DrySlide nitrocefin test (Difco Laboratories, Detroit, Mich.).
Table 1 shows the antimicrobial activities of faropenem and the comparator agents against S. pneumoniae by penicillin susceptibility status. In all, 493 (10.4%) isolates were penicillin resistant and 1,154 (24.4%) were penicillin intermediate. The MICs at which 90% of isolates are inhibited (MIC90s) were lower for faropenem and imipenem than for the other agents tested for all isolates (0.25 μg/ml). As demonstrated by other β-lactams, the activity of faropenem was affected by the penicillin susceptibility status of the isolates, with the faropenem MIC90 increasing from 0.008 μg/ml for penicillin-susceptible isolates to 1 μg/ml for penicillin-resistant isolates. Imipenem and faropenem were more active (MIC90s, 0.5 and 1 μg/ml, respectively) than amoxicillin-clavulanate, ceftriaxone, and cefuroxime (MIC,90s, 4, 4, and 16 μg/ml, respectively) against penicillin-resistant isolates. For penicillin-resistant isolates, the MIC90s of levofloxacin and SXT were 1 and >4 μg/ml, respectively. The distributions of the faropenem MICs for penicillinsusceptible, -intermediate, and -resistant isolates are compared in Table 2 with the distributions of the MICs of the other β-lactams tested. The distributions of the faropenem MICs for isolates resistant to comparator agents are provided in Table 3. For all 11 imipenem-resistant isolates, faropenem MICs were elevated (1 μg/ml). For 48 amoxicillin-clavulanate-resistant isolates, faropenem MICs ranged from 0.25 to 1 μg/ml. The ranges of MICs of faropenem were wide for 31 levofloxacin-resistant isolates (≤0.004 to 0.5 μg/ml) and for ceftriaxone-resistant, cefuroxime-resistant, penicillin-resistant, and SXT-resistant isolates (≤0.004 to 2 μg/ml).
TABLE 1.
Susceptibilities of S. pneumoniae, H. influenzae, and M. catarrhalis to faropenem and comparator antimicrobials
| Organism, antimicrobial, and phenotype | MIC (μg/ml)
|
% of isolates that werea:
|
|||||
|---|---|---|---|---|---|---|---|
| Range | Mode | 50% | 90% | S | I | R | |
| S. pneumoniaeb | |||||||
| Faropenem | |||||||
| All | ≤0.004–2 | ≤0.004 | 0.008 | 0.25 | |||
| Penicillin susceptible | ≤0.004–0.12 | ≤0.004 | ≤0.004 | 0.008 | |||
| Penicillin intermediate | ≤0.004–1 | 0.25 | 0.12 | 0.25 | |||
| Penicillin resistant | ≤0.004–2 | 0.25 | 0.5 | 1 | |||
| Amoxicillin-clavulanate | |||||||
| All | ≤0.015–16 | ≤0.015 | ≤0.015 | 1 | 95.1 | 3.9 | 1.0 |
| Penicillin susceptible | ≤0.015–1 | ≤0.015 | ≤0.015 | 0.03 | 100 | 0 | 0 |
| Penicillin intermediate | ≤0.015–4 | 1 | 0.5 | 1 | 98.3 | 1.7 | 0 |
| Penicillin resistant | 0.5–16 | 4 | 2 | 4 | 57.0 | 33.3 | 9.7 |
| Cefuroximec | |||||||
| All | ≤0.12–>32 | ≤0.12 | ≤0.12 | 4 | 73.5 | 4.8 | 21.7 |
| Penicillin susceptible | ≤0.12–1 | ≤0.12 | ≤0.12 | ≤0.12 | 100 | 0 | 0 |
| Penicillin intermediate | ≤0.12–32 | 4 | 2 | 4 | 34.1 | 19.1 | 46.8 |
| Penicillin resistant | 2–>32 | 4 | 8 | 16 | 0 | 1.2 | 98.8 |
| Imipenem | |||||||
| All | ≤0.015–1 | ≤0.015 | ≤0.015 | 0.25 | 85.3 | 14.5 | 0.2 |
| Penicillin susceptible | ≤0.015–0.25 | ≤0.015 | ≤0.015 | ≤0.015 | 99.9 | 0.1 | 0 |
| Penicillin intermediate | ≤0.015–0.5 | 0.12 | 0.12 | 0.25 | 78.6 | 21.4 | 0 |
| Penicillin resistant | 0.06–1 | 0.25 | 0.25 | 0.5 | 9.3 | 88.4 | 2.2 |
| Ceftriaxone | |||||||
| All | ≤0.015–8 | ≤0.015 | ≤0.015 | 0.5 | 90.9 | 6.2 | 2.9 |
| Penicillin susceptible | ≤0.015–0.5 | ≤0.015 | ≤0.015 | 0.03 | 100 | 0 | 0 |
| Penicillin intermediate | ≤0.015–4 | 0.5 | 0.25 | 0.5 | 92.7 | 6.2 | 1.0 |
| Penicillin resistant | 0.25–8 | 1 | 1 | 4 | 29.6 | 45.2 | 25.2 |
| Levofloxacin | |||||||
| All | ≤0.004–>8 | 1 | 1 | 1 | 99.2 | 0.1 | 0.7 |
| Penicillin susceptible | ≤0.004–>8 | 1 | 1 | 1 | 99.3 | 0.1 | 0.6 |
| Penicillin intermediate | 0.25–>8 | 1 | 1 | 1 | 99.0 | 0.3 | 0.8 |
| Penicillin resistant | 0.25–>8 | 1 | 1 | 1 | 99.4 | 0.0 | 0.6 |
| Penicillin | |||||||
| All | ≤0.03–>4 | ≤0.03 | ≤0.03 | 2 | 65.1 | 24.4 | 10.4 |
| Penicillin susceptible | ≤0.03–0.06 | ≤0.03 | ≤0.03 | ≤0.03 | 100 | 0 | 0 |
| Penicillin intermediate | 0.12–1 | 1 | 0.5 | 1 | 0 | 100 | 0 |
| Penicillin resistant | 2–>4 | 2 | 2 | 4 | 0 | 0 | 100 |
| SXT | |||||||
| All | ≤0.015–>4 | 0.25 | 0.25 | >4 | 60.8 | 7.8 | 31.3 |
| Penicillin susceptible | ≤0.015–>4 | 0.25 | 0.25 | 2 | 84.6 | 7.0 | 8.5 |
| Penicillin intermediate | 0.06–>4 | >4 | 4 | >4 | 22.3 | 11.5 | 66.2 |
| Penicillin resistant | 0.25–>4 | >4 | >4 | >4 | 3.0 | 4.5 | 92.5 |
| H. influenzaed | |||||||
| Faropenem | |||||||
| All | ≤0.004–4 | 0.25 | 0.25 | 1 | |||
| β-lactamase positive | ≤0.004–4 | 0.25 | 0.25 | 0.5 | |||
| -lactamase negative | ≤0.004–4 | 0.25 | 0.25 | 1 | |||
| Amoxicillin-clavulanate | |||||||
| All | ≤0.015–8 | 0.5 | 0.5 | 2 | >99.9 | <0.1 | |
| β-Lactamase positive | 0.03–8 | 1 | 1 | 2 | 99.9 | 0.1 | |
| β-Lactamase negative | ≤0.015–4 | 0.5 | 0.5 | 1 | 100 | 0 | |
| Cefuroximec | |||||||
| All | ≤0.12–16 | 0.5 | 0.5 | 2 | 99.9 | 0.1 | <0.1 |
| β-Lactamase positive | ≤0.12–8 | 0.5 | 0.5 | 2 | 99.9 | 0.1 | 0 |
| β-Lactamase negative | ≤0.12–16 | 0.5 | 0.5 | 2 | 99.9 | 0.1 | 0.1 |
| Imipenem | |||||||
| All | ≤0.015–4 | 0.25 | 0.5 | 1 | 100 | ||
| β-Lactamase positive | ≤0.015–4 | 0.25 | 0.5 | 1 | 100 | ||
| β-Lactamase negative | ≤0.015–4 | 0.5 | 0.5 | 1 | 100 | ||
| Ceftriaxone | |||||||
| All | ≤0.015–0.25 | ≤0.015 | ≤0.015 | ≤0.015 | 100 | ||
| β-Lactamase positive | ≤0.015–0.25 | ≤0.015 | ≤0.015 | ≤0.015 | 100 | ||
| β-Lactamase negative | ≤0.015–0.25 | ≤0.015 | ≤0.015 | ≤0.015 | 100 | ||
| Ampicillin | |||||||
| All | ≤0.06–>8 | 0.5 | 0.5 | >8 | 66.3 | 0.2 | 33.5 |
| β-Lactamase positive | 0.5–>8 | >8 | >8 | >8 | 0.1 | 0.5 | 99.4 |
| β-Lactamase negative | ≤0.06–4 | 0.5 | 0.5 | 1 | 99.8 | 0.1 | 0.1 |
| Levofloxacin | |||||||
| All | ≤0.004–0.06 | 0.015 | 0.015 | 0.015 | 100 | ||
| β-Lactamase positive | ≤0.004–0.06 | 0.015 | 0.015 | 0.015 | 100 | ||
| β-Lactamase negative | ≤0.004–0.06 | 0.015 | 0.015 | 0.015 | 100 | ||
| SXT | |||||||
| All | ≤0.015–>4 | 0.12 | 0.12 | 4 | 86.5 | 2.7 | 10.8 |
| β-Lactamase positive | ≤0.015–>4 | 0.06 | 0.12 | >4 | 82.0 | 3.1 | 14.9 |
| β-Lactamase negative | ≤0.015–>4 | 0.12 | 0.12 | 2 | 88.8 | 2.4 | 8.8 |
| M. catarrhalise | |||||||
| Faropenem | |||||||
| All | 0.008–2 | 0.5 | 0.25 | 0.5 | |||
| β-Lactamase positive | 0.008–2 | 0.5 | 0.25 | 0.5 | |||
| β-Lactamase negative | 0.015–1 | 0.03 | 0.03 | 0.12 | |||
| Amoxicillin-clavulanate | |||||||
| All | ≤0.015–1 | 0.25 | 0.25 | 0.5 | |||
| β-Lactamase positive | ≤0.015–1 | 0.25 | 0.25 | 0.5 | |||
| β-Lactamase negative | ≤0.015–0.5 | ≤0.015 | ≤0.015 | 0.03 | |||
| Cefuroxime | |||||||
| All | ≤0.12–8 | 2 | 1 | 2 | |||
| β-Lactamase positive | ≤0.12–8 | 2 | 1 | 2 | |||
| β-Lactamase negative | ≤0.12–1 | 0.25 | 0.5 | 0.5 | |||
| Imipenem | |||||||
| All | ≤0.015–0.5 | 0.12 | 0.06 | 0.12 | |||
| β-Lactamase positive | ≤0.015–0.5 | 0.12 | 0.06 | 0.12 | |||
| β-Lactamase negative | ≤0.015–0.25 | ≤0.015 | ≤0.015 | 0.03 | |||
| Ceftriaxone | |||||||
| All | ≤0.015–4 | 0.5 | 0.5 | 1 | |||
| β-Lactamase positive | ≤0.015–4 | 0.5 | 0.5 | 1 | |||
| β-Lactamase negative | ≤0.015–0.12 | ≤0.015 | ≤0.015 | ≤0.015 | |||
| Ampicillin | |||||||
| All | ≤0.06–>8 | 4 | 4 | 8 | |||
| β-Lactamase positive | ≤0.06–>8 | 4 | 4 | 8 | |||
| β-Lactamase negative | ≤0.06–0.25 | ≤0.06 | ≤0.06 | ≤0.06 | |||
| Levofloxacin | |||||||
| All | 0.015–1 | 0.03 | 0.03 | 0.06 | |||
| β-Lactamase positive | 0.015–1 | 0.03 | 0.03 | 0.06 | |||
| β-Lactamase negative | 0.03–0.25 | 0.03 | 0.03 | 0.06 | |||
| SXT | |||||||
| All | 0.06–>4 | 0.25 | 0.25 | 0.5 | |||
| β-Lactamase positive | 0.06–>4 | 0.25 | 0.25 | 0.5 | |||
| β-Lactamase negative | 0.06–0.5 | 0.12 | 0.25 | 0.25 | |||
Percentages of isolates that were susceptible (S), intermediate (I), and resistant (R) according to NCCLS breakpoints. Breakpoints are not available for faropenem.
Of the 4,725 isolates of S. pneumoniae, 3,078 were penicillin susceptible, 1,154 were penicillin intermediate, and 493 were penicillin resistant.
NCCLS breakpoints for cefuroxime axetil were used to interpret cefuroxime MICs.
A total of 2,614 isolates of H. influenzae were tested against faropenem and imipenem; 847 were β-lactamase-positive isolates and 1,767 were β-lactamase-negative isolates. Of the 2,614 isolates, 2,483 were tested against amoxicillin-clavulanate, cefuroxime, ceftriaxone, ampicillin, levofloxacin, and SXT; 834 were β-lactamase-positive isolates and 1,649 were β-lactamase-negative isolates.
A total of 1,193 isolates of M. catarrhalis were tested; 1,121 were β-lactamase-positive isolates and 72 were β-lactamase-negative isolates. NCCLS breakpoints are not available for M. catarrhalis.
TABLE 2.
Antimicrobial susceptibilities and MIC distributions for 4,725 S. pneumoniae isolates by penicillin susceptibility statusa
| Antimicrobial and phenotype | No. of isolates for which the MIC (μg/ml) was as follows:
|
||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ≤0.004 | 0.008 | ≤0.015 | 0.03 | 0.06 | ≤0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 | >32 | |
| Faropenemb | |||||||||||||||
| All | 1,655 | 1,247 | 172 | 173 | 168 | 358 | 592 | 209 | 148 | 3 | |||||
| Penicillin susceptible | 1,646 | 1,234 | 138 | 42 | 12 | 6 | |||||||||
| Penicillin intermediate | 8 | 13 | 34 | 131 | 155 | 333 | 408 | 63 | 9 | ||||||
| Penicillin resistant | 1 | 0 | 0 | 0 | 1 | 19 | 184 | 146 | 139 | 3 | |||||
| Amoxicillin-clavulanate | |||||||||||||||
| All | 2,503 | 445 | 171 | 125 | 148 | 305 | 572 | 224d | 184e | 46ff | 2 | ||||
| Penicillin susceptible | 2,490 | 427 | 113 | 36 | 7 | 4 | 1 | ||||||||
| Penicillin intermediate | 13 | 18 | 58 | 89 | 141 | 299 | 423 | 93 | 20 | ||||||
| Penicillin resistant | 2 | 148 | 131 | 164 | 46 | 2 | |||||||||
| Cefuroxime | |||||||||||||||
| All | 3,017 | 217 | 116 | 122d | 226e | 716f | 217 | 68 | 25 | 1 | |||||
| Penicillin susceptible | 2,942 | 100 | 29 | 7 | |||||||||||
| Penicillin intermediate | 75 | 117 | 87 | 115 | 220 | 486 | 50 | 3 | 1 | ||||||
| Penicillin resistant | 6 | 230 | 167 | 65 | 24 | 1 | |||||||||
| Imipenem | |||||||||||||||
| All | 3,129 | 204 | 201 | 495d | 454e | 231e | 11f | ||||||||
| Penicillin susceptible | 3,026 | 44 | 6 | 0 | 2 | ||||||||||
| Penicillin intermediate | 103 | 160 | 194 | 450 | 219 | 28 | |||||||||
| Penicillin resistant | 1 | 45 | 233 | 20 | 11 | ||||||||||
| Ceftriaxone | |||||||||||||||
| All | 2,688 | 323 | 200 | 221 | 344 | 518d | 295e | 76f | 53 | 7 | |||||
| Penicillin susceptible | 2,662 | 264 | 96 | 49 | 6 | 1 | |||||||||
| Penicillin intermediate | 26 | 59 | 104 | 172 | 332 | 377 | 72 | 8 | 4 | ||||||
| Penicillin resistant | 6 | 140 | 223 | 68 | 49 | 7 | |||||||||
Of the 4,725 isolates of S. pneumoniae, 3,078 were penicillin susceptible, 1,154 were penicillin intermediate, and 493 were penicillin resistant.
NCCLS breakpoints are not available for faropenem.
Boldface numbers represent the points at which the MIC90 was achieved.
NCCLS MIC interpretive breakpoint for susceptibility.
NCCLS MIC interpretive breakpoint for intermediate.
NCCLS MIC interpretive breakpoint for resistance.
Table 3.
Distribution of faropenem MICs for S. pneumoniae isolates resistant to comparator antimicrobials
| Drug to which isolates were resistant | No. of isolates for which the faropenem MIC (μg/ml) was as follows:
|
|||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | ≤0.004 | 0.008 | 0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | |
| Amoxicillin-clavulanate | 48 | 1 | 8 | 39a | ||||||||||
| Cefuroxime | 1,027 | 3 | 12 | 188 | 476 | 197 | 148 | 3 | ||||||
| Imipenem | 11 | 11 | ||||||||||||
| Ceftriaxone | 136 | 1 | 3 | 2 | 30 | 47 | 51 | 2 | ||||||
| Levofloxacin | 31 | 17 | 1 | 1 | 1 | 2 | 8 | 1 | ||||||
| Penicillin | 493 | 1 | 1 | 19 | 184 | 146 | 139 | 3 | ||||||
| SXT | 1,481 | 115 | 93 | 56 | 66 | 70 | 276 | 478 | 182 | 142 | 3 | |||
Boldface numbers represent the point at which the MIC90 was achieved for groups of antimicrobial-resistant isolates when 30 or more isolates were tested.
All 2,614 isolates of H. influenzae were tested for their abilities to produce β-lactamase; 847 isolates (32.4%) were β-lactamase positive and 1,767 (67.6%) were β-lactamase negative (Table 1). Faropenem and imipenem displayed equivalent activities against all isolates tested (MIC90s, 1 μg/ml). The activity of faropenem was not compromised by the production of β-lactamase; in fact, the agent was more active against β-lactamase-positive isolates than β-lactamase-negative isolates (MIC90s, 0.5 and 1 μg/ml, respectively). Ceftriaxone was the most potent agent against the H. influenzae isolates tested (n = 2,483; MIC90s, ≤0.015 μg/ml), and its activity was unaffected by β-lactamase production. There were two β-lactamase-negative, ampicillin-resistant (BLNAR) isolates in the collection of isolates tested (confirmed by repeat testing); the faropenem MICs for these two isolates were 1 and 2 μg/ml, respectively.
Of the 1,193 isolates of M. catarrhalis tested, 1,121 (94.0%) were β-lactamase positive and 72 (6.0%) were β-lactamase negative (Table 3). Imipenem was the most active β-lactam (MIC90, 0.12 μg/ml) against M. catarrhalis, followed by faropenem and amoxicillin-clavulanate (MIC90s, 0.5 μg/ml). The antimicrobial activity of faropenem was marginally compromised by the production of β-lactamase, with an MIC90 of 0.12 μg/ml for β-lactamase-negative isolates and an MIC90 of 0.5 μg/ml for β-lactamase-positive isolates.
Increasing resistance to some first-line antimicrobials has created a need for new empirical therapies for community-acquired respiratory tract infections (4, 20). Because faropenem is orally bioavailable and has been demonstrated to have in vitro activity against collections of respiratory tract pathogens of limited sizes (9, 17), it is believed to hold therapeutic promise. The present study provides faropenem susceptibility information for a far larger collection of present U.S. respiratory tract isolates and may serve as a benchmark for future studies.
Among the 4,725 S. pneumoniae isolates tested, faropenem displayed activity similar to that of imipenem, although both agents were less active against penicillin-intermediate and -resistant isolates than isolates susceptible to penicillin. The activity of faropenem against penicillin-resistant isolates of S. pneumoniae (MIC90, 1 μg/ml) was in agreement with results reported previously by Spangler et al. (19), who studied 47 penicillin-resistant S. pneumoniae isolates collected prior to and during 1994. Although the data set of Spangler et al. was small, comparison with our results suggests that there was no major change in the faropenem susceptibilities of penicillin-resistant pneumococci between 1994 and 1999. A more recent study by Black et al. also reported that faropenem had an MIC90 of 1 μg/ml for 49 penicillin-resistant pneumococcal isolates (J. A. Black et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 365, 2000).
To succeed clinically, faropenem must also be effective against β-lactamase-producing H. influenzae and M. catarrhalis strains. Sewell et al. (17) reported faropenem MIC90s of 2 μg/ml for 30 β-lactamase-positive H. influenzae isolates and 1 μg/ml for 70 β-lactamase-negative H. influenzae isolates. In contrast, we found that faropenem was more active against the 847 β-lactamase-positive isolates than the 1,767 β-lactamase-negative isolates, for which faropenem MIC90s were 0.5 and 1 μg/ml, respectively. The activity of faropenem against BLNAR isolates of H. influenzae in our study (2 isolates; MICs, 1 and 2 μg/ml) was similar to the activity reported by Felmingham et al. (12 isolates; MICs, 2 or 4 μg/ml) (D. Felmingham et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 361, 2000).
In the case of M. catarrhalis, several investigators have shown that the activity of faropenem was affected by the production of β-lactamase (17; Felmingham et al., 40th ICAAC). They found that there was at least a twofold difference between the MIC90s for β-lactamase-positive and β-lactamase-negative organisms. Comparison of the results of the present study with those of in vitro studies conducted in the mid-1990s suggests that there has been no major shift in the MIC90 of faropenem for M. catarrhalis during the last 5 years (8).
In conclusion, the present study has demonstrated that faropenem is highly active against an extensive collection of recent bacterial respiratory isolates from the United States. Faropenem had activity similar to or greater than those of the comparator agents tested and appears to hold promise for use in the therapy of community-acquired respiratory tract infections, given its oral bioavailability. However, therapeutic success will depend on its pharmacokinetic and pharmacodynamic profiles following oral administration in humans. The results of this LIBRA surveillance study may serve as a benchmark for future initiatives describing the activity of faropenem against respiratory tract pathogens in the United States.
Acknowledgments
We thank the Bayer Corporation for providing funding for this study under the auspices of the LIBRA surveillance study.
We express our appreciation to the many microbiologists and other laboratory personnel in each of the participating laboratories, without whose commitment these valuable studies would not be possible. We also thank David Diakun, Focus Technologies, Inc., Information Systems, for technical support in preparing this article.
REFERENCES
- 1.Appelbaum, P. C. 1987. World-wide development of antibiotic resistance in pneumococci. Eur. J. Clin. Microbiol. 6: 367–377. [DOI] [PubMed] [Google Scholar]
- 2.Bartlett, J. G., and L. M. Mundy. 1995. Community-acquired pneumonia. N. Engl. J. Med. 333: 1618–1624. [DOI] [PubMed] [Google Scholar]
- 3.Cormican, M. G., and R. N. Jones. 1995. Evaluation of the in vitro activity of faropenem (SY5555 or SUN5555) against respiratory tract pathogens and beta-lactamase producing bacteria. J. Antimicrob. Chemother. 35: 535–539. [DOI] [PubMed] [Google Scholar]
- 4.Doern, G. V., A. B. Brueggemann, G. Pierce, H. P. Holley, Jr., and A. Rauch. 1997. Antibiotic resistance among clinical isolates of Haemophilus influenzae in the United States in 1994 and 1995 and detection of β-lactamase-positive isolates resistant to amoxicillin-clavulanate: results of a national multicenter surveillance study. Antimicrob. Agents Chemother. 41: 292–297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Edwards, J. R. 1995. Meropenem: a microbiological overview. J. Antimicrob. Chemother. Rev. 36(Suppl A): 1–17. [DOI] [PubMed] [Google Scholar]
- 6.Felmingham, D., and J. Washington. 1999. Trends in the antimicrobial susceptibility of bacterial respiratory tract pathogens-findings of the Alexander Project 1992–1996. J. Chemother. 11(Suppl. 1): 5–21. [DOI] [PubMed] [Google Scholar]
- 7.Fluit, A. C., F. J. Schmitz, M. E. Jones, J. Acar, R. Gupta, and J. Verhoef. 1999. Antimicrobial resistance among community-acquired pneumonia isolates in Europe: first results from the SENTRY antimicrobial surveillance program 1997. SENTRY Participants Group. Int. J. Infect. Dis. 3: 153–156. [DOI] [PubMed] [Google Scholar]
- 8.Fuchs, P. C., A. L. Barry, and D. L. Sewell. 1995. Antibacterial activity of WY-49605 compared with those of six other oral agents and selection of disk content for disk diffusion susceptibility testing. Antimicrob. Agents Chemother. 39: 1472–1479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Inoue, E., and S. Mitsuhashi. 1994. In vitro antibacterial activity and beta-lactamase stability of SY5555, a new oral penem antibiotic. Antimicrob. Agents Chemother. 38: 1974–1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Klugman, K. P. 1990. Pneumococcal resistance to antibiotics. Clin. Microbiol. Rev. 3: 171–196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Miyazaki, S., T. Hosoyama, N. Furuya, Y. Ishii, T. Matsumoto, A. Ohno, K. Tateda, and K. Yamaguchi. 2001. In vitro and in vivo antibacterial activities of L-084, a novel oral carbapenem, against causative organisms of respiratory tract infections. Antimicrob. Agents Chemother. 45: 203–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Murray, P. R., E. J. Baron, M. A. Pfaller, F. C. Tenover, and R. H. Yolken (ed.). 1999. Manual of clinical microbiology, 7th ed. ASM Press, Washington, D.C.
- 13.National Committee for Clinical Laboratory Standards. 2000. Performance standards for antimicrobial susceptibility testing; 10th informational supplement, vol. 20, no. 1. M100–S10. National Committee for Clinical Laboratory Standards, Wayne, Pa.
- 14.Neu, H. C., N. X. Chin, G. Saha, and P. Labthavikul. 1986. In vitro activity against aerobic and anaerobic gram-positive and gram-negative bacteria and beta-lactamase stability of RS-533, a novel carbapenem. Antimicrob. Agents Chemother. 30: 828–834. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Nord, C. E., A. Lindmark, and I. Persson. 1989. Susceptibility of anaerobic bacteria to ALP 201. Antimicrob. Agents Chemother. 33: 2137–2139. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Okuda, J., M. Otsuki, T. Oh, and T. Nishino. 2000. In vitro activity of DU-6681a, an active form of the new oral carbapenem compound DZ-2640, in comparison with that of R-95867, faropenem and oral cephalosporins. J. Antimicrob. Chemother. 46: 101–108. [DOI] [PubMed] [Google Scholar]
- 17.Sewell, D., A. Barry, S. Allen, P. Fuchs, J. McLaughlin, and M. Pfaller. 1995. Comparative antimicrobial activities of the penem WY-49605 (SUN5555) against recent clinical isolates from five U.S. medical centers. Antimicrob. Agents Chemother. 39: 1591–1595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Spangler, S. K., M. R. Jacobs, and P. C. Appelbaum. 1994. Activity of WY-49605 compared with those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 anaerobic bacteria. Antimicrob. Agents Chemother. 38: 2599–2604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Spangler, S. K., M. R. Jacobs, and P. C. Appelbaum. 1994. In vitro susceptibilities of 185 penicillin-susceptible and -resistant pneumococci to WY-49605 (SUN/SY 5555), a new oral penem, compared with those to penicillin G, amoxicillin, amoxicillin-clavulanate, cefixime, cefaclor, cefpodoxime, cefuroxime, and cefdinir. Antimicrob. Agents Chemother. 38: 2902–2904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Thornsberry, C., M. E. Jones, M. L. Hickey, Y. Mauriz, J. Kahn, and D. F. Sahm. 1999. Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in the United States, 1997–1998. J. Antimicrob. Chemother. 44: 749–759. [DOI] [PubMed] [Google Scholar]