Activity of Faropenem against Middle Ear Fluid Pathogens from Children with Acute Otitis Media in Costa Rica and Israel

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1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 2007, p Vol. 51, No /07/$ doi: /aac Copyright 2007, American Society for Microbiology. All Rights Reserved. Activity of Faropenem against Middle Ear Fluid Pathogens from Children with Acute Otitis Media in Costa Rica and Israel Kimberley Clawson Stone, 1 Ron Dagan, 2 Adriano Arguedas, 3 Eugene Leibovitz, 2 Elaine Wang, 4 Roger M. Echols, 4 Nebojsa Janjic, 1 and Ian A. Critchley 1 * Replidyne, Inc., Louisville, Colorado ; The Pediatric Infectious Disease Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel 2 ; Instituto de Atención Pediátrica and Universidad de Ciencias Médicas, San José, Costa Rica 3 ; and Replidyne, Inc., Milford, Connecticut Received 13 January 2007/Returned for modification 27 February 2007/Accepted 14 March 2007 Faropenem was tested against 1,188 middle ear fluid pathogens from children in Israel and Costa Rica. Against Streptococcus pneumoniae and Haemophilus influenzae, faropenem was the most active -lactam, with activity that was similar to or greater than of the other oral antimicrobial classes studied. Faropenem was also active against Moraxella catarrhalis and Streptococcus pyogenes. Acute otitis media (AOM) is one of the most common respiratory tract infections in young children and a major factor behind the prescription of antibacterial agents in this population (1, 7, 15). The organisms most commonly associated with AOM are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes (11, 12, 21). Although S. pneumoniae is regarded as the most significant pathogen in recurrent AOM, nontypeable H. influenzae now appears to be taking a more prominent role as a causative pathogen because of the recent widespread use of the heptavalent conjugate vaccine in countries such as the United States (2, 3). -Lactam and macrolide antibiotics have been routinely used to manage middle ear infections, although S. pneumoniae has shown reduced susceptibility to many antibiotic classes during the last decade, with resistance rates of 20.2 and 28.9% for penicillin and azithromycin, respectively, being reported for U.S. clinical isolates in a surveillance study conducted in 2003 (13, 14). Among H. influenzae and M. catarrhalis strains, the widespread dissemination of plasmid-encoded -lactamases has largely eliminated amoxicillin as a treatment option for infections caused by -lactamase-producing strains (9), highlighting the need for new enzyme-stable -lactams. Respiratory pathogens from children are typically less susceptible to many antibacterial agents than isolates from adults (14). For example, only 45% of U.S. isolates of S. pneumoniae collected from children 2 years old were susceptible to penicillin, compared with 70% of isolates collected from adults 64 years old in the same surveillance study (14). Of the H. influenzae isolates collected in the same study, 54% of those from children 2 to 4 years old were susceptible to ampicillin, compared with 74% of those from adults 64 years old (14). Faropenem medoxomil (formerly faropenem daloxate) is an oral prodrug with excellent bioavailability (72 to 84%) that is rapidly cleaved, releasing the microbiologically active faropenem following absorption into plasma. Faropenem is active * Corresponding author. Mailing address: Replidyne Inc., 1450 Infinite Drive, Louisville, CO Phone: (303) Fax: (303) icritchley@replidyne.com. Published ahead of print on 26 March against the primary respiratory pathogens, including non-penicillin-susceptible S. pneumoniae and -lactamase-producing H. influenzae and M. catarrhalis isolates that are more prevalent in the pediatric population (5). Faropenem has demonstrated a low propensity for resistance development in both laboratory and longitudinal surveillance studies conducted over 6 years following the launch of faropenem sodium in Japan in 1997 (19). The safety profile of faropenem medoxomil is excellent, with a low incidence of diarrhea, nausea, or vomiting and no identified risk of cardiotoxicity or seizures (8; R. Echols and R. Tosiello, Abstr. 16th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. P1717, 2006; S. Gill and R. Tosiello, Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1942, 2006). Phase III clinical studies with adults have been conducted to evaluate the safety and efficacy of faropenem in treating respiratory infections such as acute bacterial sinusitis (20, 23) and community-acquired pneumonia (M. Drehobl, T. Patel, and R. Echols, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L571, 2005; A. Lentnek, A. Kelly, and R. Echols, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. L569, 2005). A pediatric formulation of faropenem sodium (dry syrup) has also been successfully developed in Japan for treating respiratory infections (10). Collectively, these properties make faropenem medoxomil an attractive candidate for studying its ability to treat respiratory tract infections in children. The objective of this surveillance study was to determine the activities of faropenem and comparator agents against baseline middle ear fluid (MEF) pathogens collected from children in previous studies conducted in Israel and Costa Rica. Although MEF isolates were collected by tympanocentesis from children 5 years old in Costa Rica and children 8 years old in Israel between 2003 and 2005, more than 90% of the isolates from both countries were from children 2 years old. During the period of isolate collection, the heptavalent conjugate vaccine was not available in Costa Rica and the subjects from Israel were not vaccinated. All isolates were shipped to a central laboratory (Replidyne, Inc., Louisville, CO), where each isolate was subcultured and reidentified by standard methods. A total of 561 isolates of S. pneumoniae, 554 isolates of H. influ- 2230

2 VOL. 51, 2007 NOTES 2231 TABLE 1. Activities of faropenem and comparator agents against MEF isolates of S. pneumoniae and H. influenzae from Israel and Costa Rica Organism, antimicrobial, and phenotype Israel Costa Rica Range 90% Range 90% S. pneumoniae b Faropenem All Penicillin susceptible Penicillin intermediate Penicillin resistant Amoxicillin-clavulanate All Penicillin susceptible Penicillin intermediate Penicillin resistant Cefdinir All Penicillin susceptible Penicillin intermediate Penicillin resistant Cefuroxime All Penicillin susceptible Penicillin intermediate Penicillin resistant Penicillin All Penicillin susceptible Penicillin intermediate Penicillin resistant Telithromycin All Penicillin susceptible Penicillin intermediate Penicillin resistant Azithromycin All Penicillin susceptible Penicillin intermediate Penicillin resistant Levofloxacin All Penicillin susceptible Penicillin intermediate Penicillin resistant SXT All Penicillin susceptible Penicillin intermediate Penicillin resistant H. influenzae c Faropenem All NA NA -Lactamase negative NA NA -Lactamase positive NA NA Amoxicillin-clavulanate All Continued on following page

3 2232 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE 1 Continued Organism, antimicrobial, and phenotype Israel Costa Rica Range 90% Range 90% -Lactamase negative Lactamase positive Cefdinir All Lactamase negative Lactamase positive Cefuroxime All Lactamase negative Lactamase positive Ampicillin All Lactamase negative Lactamase positive Telithromycin All Lactamase negative Lactamase positive Azithromycin All Lactamase negative Lactamase positive Levofloxacin All Lactamase negative Lactamase positive SXT All Lactamase negative Lactamase positive a Percentages of isolates that were susceptible according to CLSI breakpoints. Breakpoints are not available for faropenem. b Of the 393 isolates of S. pneumoniae from Israel, 154 were penicillin susceptible, 147 were penicillin intermediate, and 92 were penicillin resistant. Of the 168 isolates of S. pneumoniae from Costa Rica, 133 were penicillin susceptible, 24 were penicillin intermediate, and 11 were penicillin resistant. c Of the 367 isolates of H. influenzae from Israel, 290 were -lactamase-negative isolates and 77 were -lactamase-positive isolates. Of the 187 isolates of H. influenzae from Costa Rica, 171 were -lactamase-negative isolates and 16 were -lactamase-positive isolates. enzae, 43 isolates of M. catarrhalis, and 30 isolates of S. pyogenes were available for antimicrobial susceptibility testing. The isolates were tested for susceptibility to faropenem, ampicillin (H. influenzae and M. catarrhalis only), amoxicillinclavulanate, cefdinir, cefuroxime, penicillin (S. pneumoniae only), telithromycin, azithromycin, levofloxacin, and trimethoprim-sulfamethoxazole (SXT). Antimicrobial susceptibility testing was conducted by the broth microdilution method with frozen Sensititre panels prepared by Trek Diagnostic Systems (Cleveland, OH) in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines. For S. pneumoniae and H. influenzae, breakpoint interpretations were conducted according to the CLSI recommendations (4), with the exception of faropenem, for which no CLSI breakpoints are available. All H. influenzae and M. catarrhalis isolates were tested for the production of -lactamase by the DrySlide nitrocefin test (Difco Laboratories, Detroit, MI). The results in Table 1 show the activities of faropenem and comparator agents against MEF isolates of S. pneumoniae from Israel (n 393) and Costa Rica (n 168). Of the isolates from Israel, 154 (39.2%) were penicillin susceptible, 147 (37.4%) were penicillin intermediate, and 92 (23.4%) were penicillin resistant. Faropenem was the most active -lactam against all of the S. pneumoniae isolates from Israel, with an MIC for 90% of the isolates tested (MIC 90 )of0.5 g/ml, and was fourfold more active than amoxicillin-clavulanate (MIC 90, 2 g/ml) and eightfold more active than cefdinir and cefuroxime (MIC 90,4 g/ml). In common with other -lactams, the activity of faropenem was affected by the penicillin susceptibility status of the isolates, with the faropenem MIC 90 increasing from g/ml for penicillin-susceptible isolates to 1 g/ml for penicillin-resistant strains. Although faropenem exhibited higher MICs against penicillin-resistant S. pneumoniae, it had activity equivalent to that of telithromycin and levofloxacin (MIC 90,1 g/ml) and was more active than all of the other -lactams tested, including amoxicillin-clavulanate, cefdinir,

4 VOL. 51, 2007 NOTES 2233 TABLE 2. Antimicrobial susceptibilities and MIC distributions for MDR S. pneumoniae from Israel and Costa Rica Origin (no.) of isolates and antimicrobial(s) No. of MDR a isolates for which the was: Israel (80) Faropenem b Amoxicillin-clavulanate Cefuroxime Cefdinir Penicillin Azithromycin Telithromycin SXT c Levofloxacin Costa Rica (11) Faropenem Amoxicillin-clavulanate Cefuroxime 5 6 Cefdinir 11 Penicillin 6 5 Azithromycin Telithromycin SXT c Levofloxacin 4 7 a MDR is defined as concurrent resistance to three or more of the following antimicrobial agents: penicillin, cefuroxime or cefdinir, azithromycin, levofloxacin, and SXT. b Boldface values represent the points at which the MIC 90 was achieved. c The MIC 90 of SXT was 4 g/ml against isolates from both Israel and Costa Rica. and cefuroxime, with MIC 90 sof2,4,and8 g/ml, respectively. The least effective agents against the MEF isolates of S. pneumoniae from Israel were azithromycin and SXT, with MIC 90 s of 8 and 4 g/ml, respectively. Of the 168 S. pneumoniae isolates from Costa Rica, 133 (79.2%) were penicillin susceptible, 24 (14.3%) were penicillin intermediate, and 11 (6.5%) were penicillin resistant. The proportion of penicillin-resistant S. pneumoniae isolates was considerably lower in Costa Rica (6.5%) compared with Israel (23.4%) and was responsible for the more potent activity of faropenem against S. pneumoniae from Costa Rica (MIC 90, 0.06 g/ml) compared with isolates from Israel (MIC 90, 0.5 g/ml). Faropenem was also the most active -lactam against S. pneumoniae from Costa Rica, being twofold more active than amoxicillin-clavulanate (MIC 90, 0.12 g/ml) and fourfold more active than cefdinir and cefuroxime (MIC 90, 0.25 g/ml). With the exception of telithromycin (MIC 90, 0.06 g/ml), faropenem was the most active agent against penicillin-resistant S. pneumoniae from Costa Rica (MIC 90, 0.5 g/ml) compared with other -lactams (MIC 90 s, 2 to 8 g/ml), levofloxacin (MIC 90,1 g/ml), azithromycin (MIC 90,4 g/ml), and SXT (MIC 90, 4 g/ml). The results of this surveillance study illustrate the impact of different geographic locations on the susceptibility of clinical isolates of S. pneumoniae to faropenem and other antimicrobial agents in Israel and Costa Rica. Faropenem has also previously been evaluated in a U.S. surveillance study against a large collection of 4,725 isolates of S. pneumoniae (5), where the MIC ranges ( to 2 g/ml) were similar to those observed for isolates from Israel and Costa Rica. However, the MIC 90 of faropenem was 0.25 g/ml and was fourfold higher than for isolates from Costa Rica (0.06 g/ml) and twofold lower than for isolates from Israel (0.5 g/ml). These differences are likely to be due to the variation in the prevalence of penicillin-resistant strains in each of the different countries and also the fact that the U.S. study was not solely focused on isolates from children but also included isolates from adults. S. pneumoniae isolates from both countries were also assessed for their multidrug-resistant (MDR) phenotypes, with MDR isolates being defined as those with concurrent resistance to three or more of the following antimicrobial agents: penicillin, cefuroxime or cefdinir, azithromycin, levofloxacin, and SXT (intermediate isolates were excluded). The prevalence of MDR S. pneumoniae was 20.3% in Israel and 6.5% in Costa Rica. The distributions of the MICs of faropenem and other agents against MDR S. pneumoniae isolates are compared in Table 2. Against MDR S. pneumoniae from Israel, faropenem (MIC 90,1 g/ml) was the most active -lactam, compared with amoxicillin-clavulanate, cefdinir, and cefuroxime (MIC 90 s, 2, 8, and 8 g/ml, respectively). The activity of levofloxacin was equivalent to that of faropenem, with an MIC 90 of 1 g/ml. No levofloxacin-resistant S. pneumoniae bacteria were identified in isolates from either country, and this was not surprising since fluoroquinolones are not widely prescribed for pediatric patients. Telithromycin was the most active of the agents tested, with an MIC 90 of 0.06 g/ml, and SXT and azithromycin were the least active agents, with MIC 90 sof 4 and 8 g/ml, respectively. Faropenem was also active against the 11 MDR S. pneumoniae isolates collected from children in Costa Rica (MIC 90, 0.5 g/ml). All H. influenzae isolates from Israel (n 367) and Costa Rica (n 187) were tested for the ability to produce -lactamase. The prevalence of -lactamase-producing isolates ranged from 8.6% in Costa Rica to 20.1% in Israel. Faropenem exhibited MIC 90 s of 0.25 and 0.5 g/ml, respectively, against isolates from Israel and Costa Rica, and its activity was not

5 2234 NOTES ANTIMICROB. AGENTS CHEMOTHER. TABLE 3. Activities of faropenem and comparator agents against MEF isolates of M. catarrhalis and S. pyogenes from Costa Rica Organism and antimicrobial(s) Range For 50% of isolates For 90% of isolates M. catarrhalis a Faropenem Amoxicillin-clavulanate Cefdinir Cefuroxime Ampicillin Telithromycin Azithromycin Levofloxacin SXT S. pyogenes b Faropenem Amoxicillin-clavulanate Cefdinir Cefuroxime Penicillin Telithromycin Azithromycin Levofloxacin SXT a A total of 43 isolates of M. catarrhalis were tested. b A total of 30 isolates of S. pyogenes were tested. compromised by the ability of the organisms to produce -lactamase (Table 1). These data show that the faropenem MIC range for H. influenzae bacteria from Costa Rica and Israel ( to 2 g/ml) is similar to that for the 2,614 clinical isolates collected in a U.S. surveillance study (5). However, the MIC 90 of faropenem against the U.S. isolates was 1 g/ml and was higher than that for isolates from Costa Rica and Israel, also demonstrating the impact of the geographic location on antimicrobial susceptibility patterns. For the H. influenzae isolates from Israel, the MIC 90 sof amoxicillin-clavulanate, cefdinir, and cefuroxime were 1, 0.5, and 1 g/ml, respectively. For the isolates from Costa Rica, the MIC 90 of amoxicillin-clavulanate and cefdinir was 1 g/ml and the MIC 90 of cefuroxime was 2 g/ml. Three -lactamasenegative, ampicillin-resistant (BLNAR) isolates of H. influenzae were identified in this study; two were from Israel, and one was from Costa Rica. All three isolates were characterized by sequencing the ftsi gene that encodes PBP3 and were shown to contain the N526K substitution in PBP3 (U. Ochsner, K. Stone, C. Young, T. Hoang, N. Janjic, and I. A. Critchley, Abstr. 46th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-0036, 2006) that has also been reported in clinical isolates from France (6) and Japan (22). Faropenem exhibited an MIC of 4 g/ml against the BLNAR isolates. Although BLNAR isolates have been emerging in Japan (16, 18) and have been isolated from the nasopharynxes of Japanese children with AOM (17), they have remained rare in the United States and among the MEF isolates of H. influenzae collected from children in Israel and Costa Rica in this study (0.5% in both countries). Although all of the H. influenzae isolates from both countries were susceptible to the macrolide azithromycin, there were two isolates of H. influenzae from Costa Rica that were nonsusceptible to the ketolide telithromycin. The least effective agent against MEF isolates of H. influenzae was SXT, with MIC 90 sof 4 g/ml and only 72% of isolates from both countries being considered susceptible to the agent. The results in Table 3 show the activities of faropenem and comparator agents against MEF isolates of M. catarrhalis and S. pyogenes collected from children in Costa Rica. Against the 43 isolates of M. catarrhalis, cefdinir was the most active -lactam with an MIC 90 of 0.12 g/ml, compared with MIC 90 sof 0.25, 0.5, and 1 g/ml, for amoxicillin-clavulanate, faropenem, and cefuroxime, respectively. The most active agents against M. catarrhalis were azithromycin and levofloxacin (MIC 90 s, 0.03 g/ml) and telithromycin (MIC 90, 0.06 g/ml). All agents were active against the 30 isolates of S. pyogenes (Table 3). The MIC 90 of faropenem was g/ml, with MICs that ranged from to g/ml. All S. pyogenes isolates from Costa Rica were susceptible to azithromycin (MIC 90, 0.12 g/ml) and were inhibited by concentrations of 0.12 g/ml. 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