View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector ORIGINAL ARTICLE 10.1111/j.1469-0691.2005.01271.x Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003) T. R. Fritsche1, M. G. Stilwell1 and R. N. Jones1,2 1JMI Laboratories, North Liberty, IA and 2Tufts University School of Medicine, Boston, MA, USA ABSTRACT The spectrum of activity and potency of doripenem, a broad-spectrum parenteral carbapenem currently in clinical development, was evaluated using 16 008 clinical bacterial isolates collected as part of an international surveillance project during 2003. Using reference broth microdilution methods, doripenem was found to be highly active against oxacillin-susceptible Staphylococcus aureus and ⁄ coagulase-negative staphylococci (2705 and 297 isolates, respectively; MIC90s 0.06 mg L), with a potency greater than that of other carbapenem antibiotics. Against enterococci (1474 isolates), with the exception of Enterococcus faecium, doripenem displayed modest activity (MIC50 4). Doripenem was among the most potent agents tested against Streptococcus pneumoniae, viridans group streptococci and b ⁄ -haemolytic streptococci (885, 140 and 397 isolates; MIC90s 0.5, 0.5 and 0.03 mg L, respectively). For Enterobacteriaceae (> 6200 isolates), doripenem was four- to 32-fold more active than imipenem ⁄ against wild-type isolates (MIC90s 0.03–0.5 mg L). MIC90s for confirmed extended-spectrum b-lactamase-producing Escherichia coli and Klebsiella pneumoniae (121 and 155 isolates; 0.06 and 0.12 mg ⁄ L, respectively) were two-fold higher than for wild-type isolates. Doripenem was also active ⁄ against Citrobacter spp., Enterobacter spp. and Serratia spp. (MIC90s 0.06–0.25 mg L), including ceftazidime-resistant isolates. Doripenem and meropenem were the most active agents among all b ⁄ ⁄ ⁄ -lactams against Pseudomonas aeruginosa (829 isolates; MIC50 ⁄ 90s 0.5 8 and 0.5 16 mg L, respectively), whereas doripenem and imipenem were the most active agents against Acinetobacter spp. (155 isolates; ⁄ £ ⁄ ⁄ ⁄ MIC50 ⁄ 90s 0.5 4 and 0.5 2mg L, respectively). Doripenem was slightly more potent (MIC50 2mg L) ⁄ than ertapenem and imipenem (MIC50 4mg L), and had a potency similar to that of meropenem ⁄ (MIC50 2mg L), against Burkholderia cepacia (20 isolates). Both Haemophilus influenzae (1824 isolates) and Moraxella catarrhalis (108 isolates), including b-lactamase-positive isolates, were susceptible to ⁄ doripenem (MIC90s 0.25 and 0.03 mg L, respectively). Doripenem displays the favourable character- istics of other carbapenems, and appears to offer certain advantages in terms of potency, spectrum and b-lactamase stability when compared with some carbapenems used currently to treat nosocomial infections. Keywords Activity, antimicrobial susceptibility, carbapenems, doripenem, nosocomial infections, surveillance Original Submission: 19 April 2005; Revised Submission: 21 June 2005; Accepted: 21 July 2005 Clin Microbiol Infect 2005; 11: 974–984 selection of b-lactamase variants that now threat- INTRODUCTION en the utility of the majority of this large drug b-Lactams are among the most widely prescribed family. Enzymes have been described that have antimicrobial agents in both the community and potent hydrolytic activity against penicillins, hospital settings. Their use for over 60 years has, cephalosporins (including extended-spectrum however, resulted in a dramatic increase in the agents), cephamycins and b-lactam–inhibitor combinations [1]. The development and approval of carbapenems was a milestone in addressing Corresponding author and reprint requests: T. R. Fritsche, JMI Laboratories, Inc., 345 Beaver Kreek Centre, Suite A, North this situation, because of their broad spectrum of Liberty, IA 52317, USA activity against most Gram-positive and -negative E-mail: [email protected] pathogens, and their enhanced stability to most Ó 2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases Fritsche et al. Doripenem global surveillance 975 Ambler class A, C and D b-lactamases [2]. These MATERIALS AND METHODS agents have generally been reserved for the most Bacterial isolates tested severe infections, or for infections caused by Non-duplicate, consecutive clinical isolates were submitted organisms known to be resistant to other available from more than 70 medical centres located in North America b-lactams, especially those with an extended spec- (38.3% of isolates), South America (13.7%) and Europe (48.0%) trum of activity (third- and fourth-generation as part of the global surveillance programme for the year 2003. cephalosporins). The isolates were predominantly from patients with documen- ted bloodstream (61.9%), respiratory tract (15.5%), skin and soft Given the current emphasis on broad-spectrum tissue (7.1%) or urinary tract (9.6%) infections, and were of agents targeting Gram-positive organisms, there either nosocomial or community-acquired origin. The distribu- is a paucity of agents in development that are tion of species and number of isolates were as follows: directed at Gram-negative infections and that Enterobacteriaceae, 6240 isolates; P. aeruginosa, 829; Acinetobacter have the universal success and broad safety spp., 155; Sten. maltophilia, 80; Burkholderia cepacia, 20; Aeromonas b spp., 44; Haemophilus influenzae, 1853; Moraxella catarrhalis, 108; profiles enjoyed by -lactams. In the USA, imipe- Staphylococcus spp., 3711; Enterococcus spp., 1474; streptococci, nem and meropenem are the only carbapenems 1435 (four groups); and other Gram-positive bacteria, 59. All available that display a broad spectrum of activity isolates were included as submitted by the study participants against the important Gram-positive bacteria, and, with the single exception of vancomycin-resistant entero- cocci, were not enriched with resistant isolates. Participants Enterobacteriaceae, anaerobes and non-fermenta- were asked to submit additional isolates of vancomycin-resist- tive bacilli such as Pseudomonas aeruginosa and ant enterococci (142 isolates received) to better define the Acinetobacter spp. [3]. resistance profiles that occur within this group. Species identi- Doripenem (formerly S-4661; Shionogi Co. Ltd, fications were performed by the submitting laboratories, with Osaka, Japan) is a novel parenteral 1-b-methyl confirmation by the central coordinating laboratory (JMI Labor- atories, North Liberty, IA, USA), using established biochemical carbapenem with a molecular structure that algorithms, including the Vitek microbial identification system confers b-lactamase stability and resistance to (bioMe´rieux, Hazelwood, MO, USA). inactivation by renal dehydropeptidases [4–7]. In- vitro studies have documented those characteris- Antimicrobial susceptibility testing tics that make doripenem unique, including a All isolates were tested by the NCCLS reference broth micro- spectrum and potency against Gram-positive dilution method [19] in Mueller–Hinton broth (with the cocci which is most similar to that of imipenem, addition of lysed horse blood 2–5% v ⁄ v or Haemophilus Test and an activity against Gram-negative bacteria Medium for testing fastidious species) against a variety of antimicrobial agents representing the most common classes which is most like that of meropenem (i.e., two- and examples of drugs used in the empirical or directed to four-fold greater than that of imipenem) [8– treatment of the indicated pathogen. Dry-form microdilution 12]. A particular feature, attributed to the side panels and broth reagents were purchased from Trek Diag- chain at position 2, is greater activity against non- nostics (Cleveland, OH, USA). Doripenem standard powder fermentative Gram-negative bacilli that are multi- was provided by Peninsula Pharmaceuticals (New Brunswick, NJ, USA); other agents were acquired from their respective drug-resistant [13,14]. Unfortunately, none of the manufacturers or were purchased from Sigma Chemical Co. carbapenems is stable to the L1 enzyme pro- (St Louis, MO, USA). Interpretation of quantitative MICs was duced by Stenotrophomonas maltophilia. Doripe- in accordance with NCCLS criteria [20]. Enterobacteriaceae ‡ ⁄ ⁄ nem displays favourable pharmacokinetic, with elevated MICs ( 2mg L) for ceftazidime and or ceftri- axone and ⁄ or aztreonam were considered to have extended- pharmacodynamic and toxicological features, spectrum b-lactamase (ESBL)-producing phenotypes according similar to those of meropenem, and this promis- to NCCLS criteria [20]. ESBL confirmation was by the disk ing compound is currently in phase 3 clinical approximation method, incorporating testing with and without trials [15–17]. clavulanic acid. Quality control isolates included Escherichia coli Previous in-vitro studies have focused on lim- ATCC 25922 and ATCC 35218, P. aeruginosa ATCC 27853, H. influenzae ATCC 49247. Staphylococcus aureus ATCC 29213, ited populations of targeted species, particularly Streptococcus pneumoniae ATCC 49619 and Enterococcus faecalis resistant subsets or isolates from specific anatom- ATCC 29212 [20]. ical sites of infection, and have not presented a large geographical sampling of contemporary iso- RESULTS lates [8–11,18]. The present report summarises the results of testing doripenem and comparator Staphylococci, streptococci and enterococci agents against 16 008 Gram-positive and Gram- The activities of doripenem and ten comparison negative isolates collected as part of an interna- agents against methicillin (oxacillin)-susceptible