Antimicrobial Activity of Doripenem (S-4661): a Global Surveillance Report (2003) T

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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 characteristics 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

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 documented 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 enterococci, 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 ceftriaxone 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 tional surveillance programme during 2003.

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 976 Clinical Microbiology and Infection, Volume 11 Number 12, December 2005

S. aureus and coagulase-negative staphylococci Table 1. In-vitro activity of doripenem in comparison are shown in Table 1. Doripenem was the most with selected antimicrobial agents against Gram-positive organisms potent agent for the dilution ranges utilised compared with the other agents, including carb- MIC (mg ⁄ L) Organism ⁄ antimicrobial % % apenems, and was 32- to 64-fold more potent than agent (no. tested) 50% 90% Range susceptible resistant cefepime. Among the carbapenems tested, ⁄ Staphylococcus aureus, oxacillin-susceptible (2705) doripenem (MIC90 0.06 mg L) was two-fold more Doripenem 0.06 0.06 £ 0.008–4 –a – ⁄ Ertapenem 0.12 0.25 £ 0.06 to > 8 > 99.9 0.0 active than meropenem (MIC90 0.12 mg L) and Imipenem £ 0.5 £ 0.5 £ 0.5–4 100.0 0.0 two- to eight-fold more active than ertapenem Meropenem 0.12 0.12 0.016–4 100.0 0.0 ⁄ Cefepime 2 4 £ 0.12 to > 16 99.0 0.5 (MIC90 0.25–0.5 mg L) against the staphylococci. Ceftriaxone 4 4 0.5 to > 32 98.9 0.3 Results with isolates from different geographical Ceftazidime 8 16 £ 1 to > 16 89.2 1.2 Oxacillin 0.5 1 £ 0.06–2 100.0 0.0 regions showed minimal differences, although Piperacillin–tazobactam 1 2 £ 0.12–64 99.8 0.2 Levofloxacin 0.12 0.5 £ 0.03 to > 4 94.2 4.1 coagulase-negative staphylococci of Latin Ameri- Vancomycin 1 1 £ 0.12–4 100.0 0.0 can origin tended to display greater resistance to Coagulase-negative staphylococci, oxacillin-susceptible (297) ertapenem, while North American isolates were Doripenem 0.03 0.06 £ 0.008–8 –a – more resistant to levofloxacin (data not shown). Ertapenem 0.25 0.5 £ 0.06 to > 8 99.3 0.3 Imipenem £ 0.5 £ 0.5 £ 0.5–1 100.0 0.0 As expected, all b-lactams displayed higher MIC Meropenem 0.12 0.12 0.016–8 99.7 0.0 Cefepime 1 2 £ 0.12–8 100.0 0.0 values for oxacillin-resistant staphylococci (oxa- Ceftriaxone 2 4 £ 0.25–32 98.3 0.0 cillin-resistant staphylococci are considered resist- Ceftazidime 4 8 £ 1 to > 16 96.3 0.7 Oxacillin 0.12 0.25 £ 0.06–0.25 100.0 0.0 ant to all b-lactams), as did levofloxacin. Only Piperacillin–tazobactam 0.25 1 £ 0.12–4 100.0 0.0 Levofloxacin 0.25 2 0.06 to > 4 90.9 5.1 vancomycin remained active against all isolates. Vancomycin 1 2 0.25–4 100.0 0.0 Susceptibility testing results for Ent. faecalis and Enterococcus faecalis (1206) and other non-faecium species (70) non-faecium species revealed a small number of Doripenem 4 8 £ 0.008 to > 16 –a – isolates that were resistant to vancomycin (vanco- Ertapenem 8 > 8 £ 0.06 to > 8 – – Imipenem 1 4 £ 0.5 to > 8 – – mycin-resistant enterococci) and teicoplanin, Meropenem 8 16 £ 0.008 to > 16 – – Ceftriaxone > 32 > 32 £ 0.25 to > 32 – – occurring most commonly among North Ameri- Ampicillin 2 4 £ 1 to > 16 97.6 2.4 can isolates (8.2% and 4.0%, respectively). Piperacillin–tazobactam 4 16 £ 0.12 to > 256 –b –b Levofloxacin 1 > 4 0.12 to > 4 61.1 37.6 Doripenem was two-fold less active than imipe- Vancomycin 1 2 0.25 to > 16 92.9 5.5 Teicoplanin £ 2 £ 2 £ 2 to > 16 96.5 3.1 nem, but two-fold more potent than ertapenem or Linezolid 2 2 0.25 to > 8 99.9 0.1c meropenem, against these enterococci (Table 1). Enterococcus faecium (198) Doripenem > 16 > 16 0.03 to > 16 –a – Only 0.9% of Ent. faecalis isolates were found to be Ertapenem > 8 > 8 8 to > 8 – – Imipenem > 8 > 8 1 to > 8 – – ampicillin-resistant. One isolate from North Meropenem > 16 > 16 4 to > 16 – – America was linezolid-resistant (MIC > 8 mg ⁄ L) Ampicillin > 16 > 16 £ 1 to > 16 8.6 90.4 Ceftriaxone > 32 > 32 0.5 to > 32 – – because of a G2576U mutation, and the greatest Piperacillin–tazobactam > 256 > 256 8 to > 256 –b –b proportion (46.1%) of levofloxacin-resistant iso- Levofloxacin > 4 > 4 1 to > 4 7.1 87.3 Vancomycin > 16 > 16 0.5 to > 16 28.4 70.6 lates was found on that continent. A majority Teicoplanin > 16 > 16 £ 2 to > 16 34.0 57.4 % Linezolid 2 2 1–8 99.0 1.0 (70.6 )ofEnt. faecium isolates demonstrated Streptococcus pneumoniae (885) resistance to vancomycin, because of the inclusion Doripenem 0.016 0.5 £ 0.008–1 –a – Ertapenem £ 0.06 0.5 £ 0.06 to > 8 –d –d of 142 additional resistant isolates in the study. Imipenem £ 0.5 £ 0.5 £ 0.5–1 –d –d Meropenem 0.016 0.5 £ 0.008–2 –d –d None of the carbapenems displayed significant Cefepime £ 0.12 1 £ 0.12–4 94.9e 0.5e ‡ ⁄ £ £ e e activity (MIC90 16 mg L) against this species, Ceftriaxone 0.25 1 0.25–8 97.5 0.8 Penicillin £ 0.03 2 £ 0.03 to > 4 67.9 16.1 regardless of vancomycin susceptibility patterns. Piperacillin–tazobactam £ 0.12 4 £ 0.12–16 – – Levofloxacin 1 2 0.06 to > 4 99.9 0.1 The most active antimicrobial agent among those Vancomycin 0.25 0.5 £ 0.06–1 100.0 – tested against Ent. faecium was linezolid (99.0% Erythromycin £ 0.25 16 £ 0.25 to > 32 73.8 25.5 Viridans group streptococcif (140) susceptible). Doripenem 0.03 0.5 £ 0.008 to > 16 –a – The population of Strep. pneumoniae tested Ertapenem 0.12 1 £ 0.06–4 – – Imipenem £ 0.5 £ 0.5 £ 0.5–4 –– included 32.1% of isolates that were non-suscept- Meropenem 0.06 0.5 £ 0.008 to > 16 90.7 – % Cefepime 0.25 1 £ 0.12–8 90.7 1.4 ible to penicillin, and 25.5 that were resistant to Ceftriaxone £ 0.25 1 £ 0.25–8 90.7 2.9 erythromycin; the carbapenems and vancomycin Penicillin 0.06 2 £ 0.016–32 65.7 7.9 £ Piperacillin–tazobactam 0.25 4 £ 0.12 to > 256 – – were the most active agents tested (MIC90s Levofloxacin 1 2 0.06 to > 4 99.3 0.7 ⁄ Vancomycin 0.5 1 £ 0.12–2 99.3 – 0.5 mg L). Resistance to some agents varied Erythromycin £ 0.06 4 £ 0.06 to > 8 55.0 40.0 significantly according to geographical region,

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 Fritsche et al. Doripenem global surveillance 977

Table 1. Continued Other Gram-positive species MIC (mg ⁄ L) Doripenem was slightly less active against Micro- Organism ⁄ antimicrobial % % agent (no. tested) 50% 90% Range susceptible resistant coccus spp. (13 isolates) than against staphylococci ⁄ (MIC50 ⁄ 90s 0.06 and 0.12 mg L, respectively), and b-Haemolytic streptococci (397) Doripenem £ 0.008 0.03 £ 0.008–0.25 –a – was similar in potency to meropenem. Only Ertapenem £ 0.06 £ 0.06 £ 0.06–1 100.0 – Imipenem £ 0.5 £ 0.5 £ 0.5–1 – – vancomycin among the selected agents was uni- Meropenem £ 0.008 0.06 £ 0.008–0.5 100.0 – formly active in vitro against Corynebacterium spp. Cefepime £ 0.12 £ 0.12 £ 0.12–16 99.5 – ⁄ Ceftriaxone £ 0.25 £ 0.25 £ 0.25–16 99.2 – (17 isolates; MIC range 0.25–1 mg L); all carbap- Penicillin £ 0.016 0.06 £ 0.016–1 99.7 – enems had high MIC values (‡ 16 mg ⁄ L). Bacil- Piperacillin–tazobactam £ 0.12 0.5 £ 0.12–4 – – 90 Levofloxacin 0.5 1 £ 0.03–2 100.0 0.0 lus spp. (12 isolates) were more susceptible to Vancomycin 0.25 0.5 £ 0.12–1 100.0 0.0 ⁄ ⁄ doripenem (MIC50 ⁄ 90 0.06 4mg L), which was aNo breakpoints have been established by the NCCLS [20]. two- to four-fold more potent than the other bSusceptibility is predicted by the ampicillin result [20]. cOne strain with G2576U mutation. carbapenems. Only levofloxacin and vancomycin dNon-meningitis breakpoints are not established [20]. eBased upon non-meningitis breakpoints [20]. among selected comparators were consistently fIncludes Strep. mitis (33 isolates), Strep. anginosus (14), Strep. sanguis (10), Strep. oralis more active. Doripenem and meropenem were (nine), Strep. constellatus (eight), Strep. milleri (seven), Strep. salivarius (seven) and ⁄ others (52). equally active (MIC50 ⁄ 90s 0.12 and 0.25 mg L) against Listeria spp. (17 isolates), and were more active than penicillin, levofloxacin and vancomy- ⁄ with penicillin and erythromycin resistance vary- cin (MIC90s 0.5, 1 and 1 mg L, respectively). ing from 14.1% and 15.1% in Latin America to 19.9% and 31.2%, respectively, in North America Enterobacteriaceae (data not shown). All isolates (100%) and 99.9% of isolates were susceptible to vancomycin and The spectrum and activity of doripenem and levofloxacin, respectively. comparator agents against Enterobacteriaceae are Against viridans group streptococci, doripe- listed in Table 2. Almost 50% of the E. coli isolates ⁄ % nem (MIC50 0.03 mg L) was two-fold more act- were ampicillin-resistant, and c.13 were resist- ive than meropenem, and four-fold more active ant to levofloxacin (10.2% in North America, than ertapenem (Table 1). There were 7.9% 22.6% in Latin America, and 11.9% in Europe). penicillin-resistant isolates, with smaller percent- However, > 99.9% of isolates remained suscept- ages also being resistant to ceftriaxone (2.9%) ible to the carbapenems. Isolates from Europe had and cefepime (1.4%). Penicillin resistance was a similar antibiogram to those from the USA, greatest in Latin America (23.1%) and least in whereas those from Latin America were more Europe (6.0%), whereas erythromycin resistance resistant to ampicillin, third-generation cephalo- was greatest in Europe (44.8%) and least in sporins and fluoroquinolones (data not shown). In Latin America (23.1%; data not shown). Strepto- total, 121 isolates of E. coli were confirmed as coccus bovis (13 isolates) had an antibiogram ESBL producers by the clavulanate inhibition test most similar to that of viridans group strepto- (4.0% of the total E. coli collection tested). The cocci, although the carbapenems, particularly prevalence of ESBL-producing E. coli in North doripenem and meropenem, displayed greater America, Latin America and Europe was 1.5%, potency (MIC for all strains £ 0.016 mg ⁄ L). The 8.9% and 4.6%, respectively. Potencies of all Strep. bovis isolates were also susceptible to selected agents, including fluoroquinolones, were penicillin. decreased markedly among ESBL producers, with £ Doripenem exhibited activity (MIC50 the exception of the carbapenems. Doripenem 0.008 mg ⁄ L) equal to or greater to that of penicil- displayed a potency against the ESBL producers ⁄ lin and the other carbapenems for the dilution (MIC90 0.06 mg L) that was one dilution higher ranges tested against b-haemolytic streptococci than that against the wild-type population ⁄ (groups A, B, C, F and G). All agents with (MIC90 0.03 mg L). established breakpoints displayed > 99% sus- Against Klebsiella spp., the potency of doripe- ceptibility rates, with ertapenem, meropenem, nem was comparable to that of meropenem and levofloxacin and vancomycin showing 100% sus- the other carbapenems, given the dilution sched- ceptibility. ules utilised, with ‡ 98.8% of isolates being

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 978 Clinical Microbiology and Infection, Volume 11 Number 12, December 2005

Table 2. In-vitro activity of doripenem in comparison Table 2. Continued with selected antimicrobial agents against contemporary ⁄ wild-type isolates of Enterobacteriaceae MIC (mg L) Organism ⁄ antimicrobial % % agent (no. tested) 50% 90% Range susceptible resistant MIC (mg ⁄ L) Organism ⁄ antimicrobial % % Proteus mirabilis (307) agent (no. tested) 50% 90% Range susceptible resistant Doripenem 0.12 0.25 0.016–0.5 –a – Ertapenem £ 0.06 £ 0.06 £ 0.06–4 99.6 0.0 Escherichia coli (3023) Imipenem 1 2 £ 0.5–8 99.7 0.0 £ a Doripenem 0.03 0.03 0.008–1 – – Meropenem 0.06 0.06 0.016–1 100.0 0.0 £ £ £ Ertapenem 0.06 0.06 0.06–4 99.9 0.0 Cefepime £ 0.12 £ 0.12 £ 0.12 to > 16 98.0 1.6 £ £ £ Imipenem 0.5 0.5 0.5 to > 8 > 99.9 < 0.1 Ceftriaxone £ 0.25 £ 0.25 £ 0.25 to > 32 96.7 1.6 £ Meropenem 0.016 0.03 0.008–2 100.0 0.0 Ceftazidime £ 1 £ 1 £ 1 to > 16 98.4 0.7 £ £ £ Cefepime 0.12 0.12 0.12 to > 16 97.6 2.0 Ampicillin 2 > 16 £ 1 to > 16 71.3 26.7 £ £ £ b Ceftriaxone 0.25 0.25 0.25 to > 32 96.5 3.0 (4.5) Ampicillin–sulbactam 1 32 0.5 to > 32 84.7 10.1 £ £ £ b Ceftazidime 1 1 1 to > 16 97.2 1.7 (5.1) Piperacillin–tazobactam 0.25 1 £ 0.12–64 98.4 0.0 £ Ampicillin 8 > 16 1 to > 16 50.2 48.6 Levofloxacin 0.06 > 4 £ 0.03 to > 4 86.0 10.1 £ Ampicillin–sulbactam 4 > 32 0.25 to > 32 56.4 25.3 Indole-positive Proteae (148) £ Piperacillin–tazobactam 2 4 0.12 to > 256 97.3 1.4 Doripenem 0.12 0.5 0.03–1 –a – £ £ Levofloxacin 0.03 > 4 0.03 to > 4 85.6 12.6 Ertapenem £ 0.06 £ 0.06 £ 0.06–0.12 100.0 0.0 E. coli (ESBL-confirmed; 121) £ a Imipenem 2 4 0.5–4 100.0 0.0 Doripenem 0.03 0.06 0.016–1 – – Meropenem 0.06 0.12 0.016–0.5 100.0 0.0 £ £ Ertapenem 0.06 0.25 0.06–4 99.1 0.0 Cefepime £ 0.12 0.25 £ 0.12 to > 16 99.3 0.7 £ £ £ Imipenem 0.5 0.5 0.5 100.0 0.0 Ceftriaxone £ 0.25 2 £ 0.25 to > 32 97.3 0.7 Meropenem 0.03 0.06 0.016–2 100.0 0.0 Ceftazidime £ 14 £ 1 to > 16 94.6 1.4 £ Cefepime 16 > 16 0.12 to > 16 43.0 47.9 Ampicillin > 16 > 16 £ 1 to > 16 8.1 87.2 £ Ceftriaxone > 32 > 32 0.25 to > 32 24.8 70.2 Ampicillin–sulbactam 16 32 0.5 to > 32 30.4 31.1 £ Ceftazidime 16 > 16 1 to > 16 47.1 32.2 Piperacillin–tazobactam 0.5 4 £ 0.12–64 99.3 0.0 Ampicillin > 16 > 16 16 to > 16 0.0 99.2 Levofloxacin 0.06 4 £ 0.03 to > 4 86.5 9.5 Ampicillin–sulbactam 32 > 32 2 to > 32 4.1 88.4 Serratia spp. (187) Piperacillin–tazobactam 8 128 0.5 to > 256 80.2 13.2 Doripenem 0.12 0.25 0.03–1 –a – £ Levofloxacin > 4 > 4 0.03 to > 4 34.7 61.2 Ertapenem £ 0.06 0.12 £ 0.06–0.5 100.0 0.0 Klebsiella spp. (1107) £ £ a Imipenem 0.5 1 0.5–8 99.5 0.0 Doripenem 0.03 0.06 0.016 to > 16 – – Meropenem 0.03 0.06 0.016–0.25 100.0 0.0 £ £ £ Ertapenem 0.06 0.06 0.06 to > 8 98.8 0.8 Cefepime £ 0.12 0.5 £ 0.12 to > 16 95.7 4.3 £ £ £ Imipenem 0.5 0.5 0.5 to > 8 99.7 0.3 Ceftriaxone £ 0.25 16 £ 0.25 to > 32 89.8 5.4 £ Meropenem 0.03 0.03 0.008 to > 16 99.6 0.2 Ceftazidime £ 1 £ 1 £ 1 to > 16 94.6 3.8 £ £ Cefepime 0.12 4 0.12 to > 16 92.3 6.1 Ampicillin > 16 > 16 4 to > 16 4.3 88.7 £ £ b Ceftriaxone 0.25 32 0.25 to > 32 85.5 9.8 (16.9) Ampicillin–sulbactam 32 > 32 4 to > 32 7.5 74.7 £ £ b Ceftazidime 116 1–16 89.3 8.6 (15.9) Piperacillin–tazobactam 2 32 0.5 to > 256 89.8 1.6 £ Ampicillin > 16 > 16 1 to > 16 5.6 78.0 Levofloxacin 0.12 1 £ 0.03 to > 4 93.5 3.8 £ Ampicillin–sulbactam 8 > 32 0.25 to > 32 70.5 22.4 Salmonella spp. (530) £ Piperacillin–tazobactam 2 32 0.12 to > 256 88.2 8.6 Doripenem 0.06 0.06 0.016–0.25 –a – £ Levofloxacin 0.06 2 0.03 to > 4 90.8 7.1 Ertapenem £ 0.06 £ 0.06 £ 0.06–0.12 100.0 0.0 Klebsiella spp. (ESBL-confirmed; 155) £ £ £ a Imipenem 0.5 0.5 0.5–2 100.0 0.0 Doripenem 0.06 0.12 0.016–8 – – Meropenem 0.03 0.03 0.016–0.5 100.0 0.0 £ £ Ertapenem 0.06 0.5 0.06 to > 8 97.9 1.4 Cefepime £ 0.12 £ 0.12 £ 0.12 to > 16 97.4 0.6 £ £ £ Imipenem 0.5 0.5 0.5–2 100.0 0.0 Ceftriaxone £ 0.25 £ 0.25 £ 0.25 to > 32 96.6 3.0 Meropenem 0.03 0.12 0.016–2 100.0 0.0 Ceftazidime £ 1 £ 1 £ 1 to > 16 99.4 0.4 £ Cefepime 8 > 16 0.12 to > 16 54.2 35.5 Ampicillin 2 > 16 £ 1 to > 16 75.8 23.4 £ Ceftriaxone > 32 > 32 0.25 to > 32 11.6 60.6 Ampicillin–sulbactam 2 32 £ 0.25 to > 32 80.6 15.7 £ Ceftazidime > 16 > 16 1 to > 16 36.8 51.6 Piperacillin–tazobactam 4 4 0.5 to > 256 96.0 3.6 Ampicillin > 16 > 16 > 16 0.0 100.0 Levofloxacin 0.06 0.25 £ 0.03–4 99.8 0.0 Ampicillin–sulbactam > 32 > 32 0.5 to > 32 5.2 85.8 Shigella spp. (161) Piperacillin–tazobactam 8 > 256 0.25 to > 256 60.0 31.0 Doripenem 0.03 0.06 0.016–0.06 –a – £ Levofloxacin 0.5 > 4 0.03 to > 4 65.2 28.4 Ertapenem £ 0.06 £ 0.06 £ 0.06 100.0 0.0 Enterobacter spp. (601) Imipenem £ 0.5 £ 0.5 £ 0.5 100.0 0.0 £ a Doripenem 0.06 0.12 0.008–4 – – Meropenem 0.03 0.03 0.016–0.03 100.0 0.0 £ £ Ertapenem 0.06 1 0.06 to > 8 96.8 1.3 Cefepime 0.25 0.5 £ 0.12–1 100.0 0.0 £ £ Imipenem 0.5 1 0.5 to > 8 99.7 0.2 Ceftriaxone £ 0.25 £ 0.25 £ 0.25–1 100.0 0.0 £ Meropenem 0.03 0.12 0.008–8 99.8 0.4 Ceftazidime £ 1 £ 1 £ 1 100.0 0.0 £ £ Cefepime 0.12 4 0.12 to > 16 95.7 3.2 Ampicillin > 16 > 16 £ 1 to > 16 22.4 77.6 £ £ Ceftriaxone 0.25 > 32 0.25 to > 32 77.5 14.7 Ampicillin–sulbactam 32 32 1 to > 32 22.4 52.2 £ £ Ceftazidime 1>16 1 to > 16 76.0 20.5 Piperacillin–tazobactam 2 4 0.25–8 100.0 0.0 Ampicillin > 16 > 16 2 to > 16 5.3 88.0 Levofloxacin £ 0.03 £ 0.03 £ 0.03–1 100.0 0.0 Ampicillin–sulbactam 32 > 32 1 to > 32 22.0 56.8 £ Piperacillin–tazobactam 2 64 0.12 to > 256 81.4 8.7 aNo breakpoints have been established by the NCCLS [20]. £ Levofloxacin 0.06 > 4 0.03 to > 4 87.5 10.5 bPercentages in parentheses indicate those isolates meeting the NCCLS screening Citrobacter spp. (136) criteria (MIC ‡ 2mg⁄ L) for an ESBL-producing isolate [20]. Doripenem 0.03 0.06 £ 0.008–2 –a – Ertapenem £ 0.06 0.12 £ 0.06–4 99.2 0.0 Imipenem £ 0.5 1 £ 0.5 to > 8 99.3 0.7 Meropenem 0.03 0.06 £ 0.008–4 100.0 0.0 susceptible. Geographical differences in the Cefepime £ 0.12 1 £ 0.12 to > 16 97.8 2.2 Klebsiella spp. antibiogram (decreased activity Ceftriaxone £ 0.25 16 £ 0.25 to > 32 87.5 4.4 Ceftazidime £ 1>16£ 1 to > 16 88.2 11.0 against third-generation cephalosporins) were Ampicillin > 16 > 16 2 to > 16 10.3 77.2 Ampicillin–sulbactam 8 > 32 2 to > 32 64.0 23.5 caused primarily by the presence of confirmed Piperacillin–tazobactam 2 32 0.5 to > 256 88.2 4.4 ESBL-producing isolates, which comprised 14% Levofloxacin £ 0.03 2 £ 0.03 to > 4 91.2 6.6 of isolates overall, and which were most preval-

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 Fritsche et al. Doripenem global surveillance 979 ent in Latin America (28.6%), followed by ible to all selected agents, with the exceptions Europe (15.6%) and North America (6.9%). The of ampicillin (75.8%) and ampicillin–sulbactam % doripenem MIC50 ⁄ 90s for ESBL-confirmed isolates (80.6 ). Most Shigella spp. were resistant to were both only two-fold higher than those for the ampicillin (77.6%) and ampicillin–sulbactam % entire population; however, the MIC90 of ertape- (52.2 ), but were otherwise susceptible to all nem was eight-fold higher, while that of other selected agents. The highest doripenem imipenem remained essentially unchanged. The MIC for the Salmonella and Shigella spp. was inhibitor combinations ampicillin–sulbactam and 0.06 mg ⁄ L (Table 2). piperacillin–tazobactam had markedly reduced activity for the ESBL subset, as did levofloxacin Non-fermentative Gram-negative bacilli and (Table 2). Aeromonas spp. Enterobacter spp. were susceptible to carbapenems, with doripenem and meropenem having Doripenem was the most active agent (MIC90 8 ⁄ ⁄ an identical MIC90 (0.12 mg L), making them mg L) among the carbapenems against wild- eight-fold more active than either ertapenem or type P. aeruginosa (Table 3), being slightly ⁄ imipenem. Third- and fourth-generation cephalo- more potent than meropenem (MIC90 16 mg L), ⁄ sporins, piperacillin–tazobactam and levofloxacin imipenem and ertapenem (MIC90 >8mg L). all showed varying degrees of activity against Resistance in P. aeruginosa to all tested carba- Enterobacter spp. (76.0–95.7% susceptibility). Like- penems was lowest in North America (2–6%), wise, doripenem and meropenem were the most intermediate in Europe (8–15%) and highest in ⁄ ⁄ % active compounds (MIC50 ⁄ 90s0.03 0.06 mg L) Latin America (10–21 ), based upon proposed against Citrobacter spp. (136 isolates). Among tentative breakpoints for doripenem, which the carbapenems, imipenem was least active are identical to those of other carbapenems ⁄ % (MIC90 1mg L), although 99.3 of isolates (Table 4). The greatest resistance to other agents remained susceptible. Cefepime and levofloxacin was observed for ceftriaxone (75.8%), levofloxa- were the next most active agents tested (97.8% cin (27.5%), aztreonam (21.7%), tobramycin and 91.2% susceptible; Table 2). (21.5%), ceftazidime (19.2%) and piperacillin– % The MIC90 of doripenem for Proteus mirabilis tazobactam (18.2 ). was slightly higher than that of meropenem Imipenem was the most active carbapenem ⁄ £ ⁄ ⁄ (MIC90s 0.25 and 0.06 mg L, respectively); how- (MIC50 ⁄ 90 0.5 2mg L) tested against Acineto- ever, the highest doripenem MIC was only bacter spp. (Table 3). Doripenem (MIC50 ⁄ 90 ⁄ ⁄ ⁄ ⁄ 0.5 mg L, compared with 1 mg L for merope- 0.5 4mg L) and meropenem (MIC50 ⁄ 90 nem. Ertapenem was slightly more active 1 ⁄ 8mg⁄ L) were also active against these wild- £ ⁄ (MIC90 0.06 mg L), although the range extend- type isolates, whereas ertapenem displayed ⁄ ⁄ ⁄ ed to 4 mg L. Rates of resistance to ampicillin marginal activity (MIC50 ⁄ 90 4 >8mg L). Among (26.7%), ampicillin–sulbactam (10.1%) and levo- other agents tested, tobramycin was the most % ⁄ % floxacin (10.1 ) were elevated. Piperacillin–tazo- active compound (MIC50 1mg L; 67.7 suscept- ⁄ % bactam was similar in activity to the carbapenems ible), with cefepime (MIC50 8mg L; 57.4 % ⁄ (98.4 susceptible). The agents demonstrating susceptible), levofloxacin (MIC50 0.5 mg L; greatest activity against indole-positive Proteae 57.4% susceptible) and piperacillin–tazobactam ⁄ % (four species), in decreasing order by MIC90s, (MIC50 32 mg L; 49.7 susceptible) also retaining were: ertapenem (£ 0.06 mg ⁄ L) > meropenem some activity. As with P. aeruginosa, Latin Ameri- (0.12 mg ⁄ L) > cefepime (0.25 mg ⁄ L) > doripenem can isolates of Acinetobacter spp. tended to display (0.5 mg ⁄ L) > imipenem = ceftazidime = pipera- much greater resistance to all drug classes, espe- cillin–tazobactam = levofloxacin (4 mg ⁄ L). cially tobramycin (data not shown). Against Serratia spp., doripenem, ertapenem Among other Gram-negative bacilli investi- and meropenem were the most active agents gated, B. cepacia isolates were variable in ⁄ tested, with MIC90s of 0.25, 0.12 and 0.06 mg L, their patterns of susceptibility to carbapenems, respectively, and ‡ 99.5% susceptibility rates. with meropenem being most active ⁄ ⁄ % Cefepime, ceftazidime and levofloxacin also dem- (MIC50 ⁄ 90 2 4mg L; 90.0 susceptible), followed % ⁄ ⁄ onstrated > 90 susceptibility among the selected by doripenem (MIC50 ⁄ 90 2 8mg L) and imipenem % ⁄ ⁄ % comparators. Salmonella spp. were > 95 suscept- (MIC50 ⁄ 90 4 8mg L; 65.0 susceptible). Ceftazi-

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 980 Clinical Microbiology and Infection, Volume 11 Number 12, December 2005

Table 3. In-vitro activity of doripenem in comparison Table 4. Cumulative percentage of Pseudomonas aeruginosa with selected antimicrobial agents against isolates of non- isolates from different geographical regions susceptible to fermentative Gram-negative bacilli and Aeromonas spp. each carbapenem concentration

MIC (mg ⁄ L) Cumulative % of isolates susceptible to each conc. ⁄ Organism ⁄ antimicrobial % % (mg L) agent (no. tested) 50% 90% Range susceptible resistant Region ⁄ antimicrobial agent (no. isolates) £ 0.51248‡ 16 Pseudomonas aeruginosa (829) Doripenem 0.5 8 0.03 to > 16 –a – North America (226) Ertapenem 8 > 8 0.12 to > 8 – – Doripenem 69 87 92 96 98 100 Imipenem 1 > 8 £ 0.5 to > 8 80.7 13.5 Meropenem 66 84 90 93 96 100 Meropenem 0.5 16 0.016 to > 16 83.5 11.7 Imipenem 15 69 89 91 94 100 Cefepime 4 > 16 £ 0.12 to > 16 76.6 11.6 Europe (450) Ceftriaxone > 32 > 32 0.5 to > 32 7.2 75.8 Doripenem 53 73 79 86 92 100 Ceftazidime 4 > 16 £ 1 to > 16 75.0 19.2 Meropenem 54 68 75 83 88 100 Piperacillin–tazobactam 8 256 £ 0.12 to > 256 81.8 18.2 Imipenem 11 59 74 80 85 100 Aztreonam 8 > 16 0.25 to > 16 64.3 21.7 Latin America (153) Levofloxacin 0.5 > 4 0.06 to > 4 69.0 27.5 Doripenem 44 59 65 76 90 100 Tobramycin 0.5 > 16 £ 0.12 to > 16 77.3 21.5 Meropenem 42 56 63 71 79 100 Acinetobacter spp. (155) Imipenem 11 51 65 67 79 100 Doripenem 0.5 4 0.016 to > 16 –a – Ertapenem 4 > 8 £ 0.06 to > 8 – – Imipenem £ 0.5 2 £ 0.5 to > 8 92.3 7.1 Meropenem 1 8 £ 0.016 to > 16 89.7 7.7 Cefepime 8 > 16 £ 0.12 to > 16 57.4 29.7 very resistant to the agents tested, particularly Ceftriaxone 32 > 32 £ 0.25 to > 32 31.0 40.6 % Ceftazidime 8 > 16 £ 1 to > 16 52.3 37.1 carbapenems (83.5–98.7 resistant). Levofloxacin Piperacillin–tazobactam 32 > 256 £ 0.12 to > 256 49.7 43.9 (87.5% susceptible) was the most active agent, Aztreonam > 16 > 16 £ 0.12 to > 16 9.0 74.2 Levofloxacin 0.5 > 4 £ 0.03 to > 4 57.4 38.1 followed by ceftazidime (56.3%). Tobramycin 1 > 16 £ 0.12 to > 16 67.7 26.5 Burkholderia cepacia (20) Aeromonas spp. were generally susceptible Doripenem 2 8 0.12 to > 16 –a – (> 93.0%) to all agents tested, except for piperacil- Ertapenem 4 8 £ 0.06 to > 8 – – % Imipenem 4 8 £ 0.5 to > 8 65.0 10.0 lin–tazobactam (60.5 ). All carbapenems had Meropenem 2 4 0.06 to > 16 90.0 10.0 similar activity (MIC 1–2 mg ⁄ L) against Aero- Cefepime 8 16 £ 0.12 to > 16 85.0 10.0 90 Ceftriaxone 16 > 32 £ 0.25 to > 32 35.0 20.0 monas spp. Ceftazidime 4 4 £ 1 to > 16 90.0 10.0 Piperacillin–tazobactam 4 256 0.5 to > 256 80.0 15.0 Aztreonam 16 > 16 £ 0.12 to > 16 40.0 20.0 Levofloxacin 1 4 £ 0.3 to > 4 80.0 10.0 Fastidious respiratory tract pathogens Tobramycin > 16 > 16 £ 0.12 to > 16 15.0 75.0 Stenotrophomonas maltophilia (80) Doripenem > 16 > 16 1 to > 16 –a – Meropenem was slightly more active than ⁄ ⁄ Ertapenem > 8 > 8 1 to > 8 – – doripenem (MIC50 ⁄ 90s 0.03 0.12 and 0.06 0.25 Imipenem > 8 > 8 2 to > 8 1.3 98.7 Meropenem > 16 > 16 0.5 to > 16 5.1 83.5 mg ⁄ L, respectively) against H. influenzae (both Cefepime 16 > 16 1 to > 16 21.3 42.5 b Ceftriaxone > 32 > 32 2 to > 32 2.5 91.2 -lactamase-positive and -negative phenotypes; Ceftazidime 8 > 16 £ 1 to > 16 56.3 35.0 Table 5). The adverse effects of the TEM Piperacillin–tazobactam 256 > 256 8 to > 256 5.0 56.2 b Aztreonam > 16 > 16 4 to > 16 3.8 91.2 enzyme in -lactamase-positive isolates on the Levofloxacin 1 4 0.12 to > 4 87.5 3.7 activity of the carbapenems was minimal. The Tobramycin > 16 > 16 1 to > 16 11.3 72.5 Aeromonas spp. (44) b-lactamase-positive rate among H. influenzae Doripenem 0.5 1 0.03–4 –a – % b Ertapenem 0.25 1 £ 0.06 to > 8 – – isolates was 21.8 , but the number of -lacta- Imipenem £ 0.5 2 £ 0.5 to > 8 93.2 2.3 mase-negative ampicillin-resistant isolates was Meropenem 0.12 1 0.016–4 97.7 0.0 Cefepime £ 0.12 0.25 £ 0.12–4 100.0 0.0 only 0.1% (Table 5). All other agents tested also Ceftriaxone £ 0.25 1 £ 0.25–32 97.7 0.0 % Ceftazidime £ 1 £ 1 £ 1 to > 16 97.7 2.3 exhibited potent activity (> 94 susceptibility) Piperacillin–tazobactam 8 128 1–256 60.5 11.6 against H. influenzae, with the exceptions of Aztreonam £ 0.12 0.25 £ 0.12–2 100.0 0.0 % Levofloxacin £ 0.03 0.25 £ 0.03 to > 4 97.7 2.3 trimethoprim–sulphamethoxazole (75.6–83.5 ) Tobramycin 1 4 0.25 to > 16 93.2 6.8 and clarithromycin (80.9–86.7%). Against aNo breakpoints have been established by the NCCLS [20]. M. catarrhalis, doripenem and the comparators tested showed potent activity, with the expected exception of penicillin. b-Lactamase production dime and cefepime were also active (90% and 85% was demonstrated for all but five (95.3%) of the of isolates susceptible), followed by piperacillin– isolates with a chromogenic cephalosporin test. % £ tazobactam and levofloxacin (both showing 80 Doripenem was more potent (MIC50 ⁄ 90 susceptibility). Resistance was most pronounced 0.016 ⁄ 0.03 mg ⁄ L) than the fluoroquinolones with tobramycin (75%), aztreonam (20%) and (ciprofloxacin and levofloxacin), and showed ceftriaxone (20%). Sten. maltophilia isolates were superior activity when compared with the

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 Fritsche et al. Doripenem global surveillance 981

Table 5. In-vitro activity of doripenem in comparison doripenem retained the greatest potency among with selected antimicrobial agents against isolates of carbapenems against ESBL- and AmpC-produc- Haemophilus influenzae and Moraxella catarrhalis ing enteric bacilli, as well as against penicillin- MIC (mg ⁄ L) resistant Strep. pneumoniae [9]. Also, a greater Organism ⁄ antimicrobial % % agent (no. tested) 50% 90% Range susceptible resistant proportion of carbapenem-resistant P. aeruginosa and Acinetobacter spp. isolates were inhibited by H. influenzae, b-lactamase- £ ⁄ negative (1426) doripenem at 4mg L [7–9]. When compared Doripenem 0.06 0.25 £ 0.008–2 –a – with several other anti-pseudomonal agents, Meropenem 0.03 0.12 £ 0.008–0.25 100.0 – Cefepime £ 0.06 0.12 £ 0.06 to > 8 99.8 – including other carbapenems, doripenem was Ceftriaxone £ 0.008 0.016 £ 0.008 to > 16 99.9 – Ampicillin £ 0.5 1 £ 0.5 to > 4 99.6 0.1 associated with the lowest rate of spontaneous Ciprofloxacin £ 0.12 £ 0.12 £ 0.12 to > 16 99.9 – resistance [13]. Levofloxacin £ 0.03 £ 0.03 £ 0.03–0.12 100.0 – Trimethoprim– £ 0.5 > 4 £ 0.5 to > 4 83.5 14.7 The aim of the present study was to character- sulphamethoxazole ise the global antibiogram for doripenem and Clarithromycin 8 16 £ 0.25 to > 32 86.7 1.1 Tetracycline £ 2 £ 2 £ 2 to > 16 99.2 0.6 other agents used in similar clinical circum- H. influenzae, b-lactamase- positive (398) stances. For a large (16 008 isolates) collection of Doripenem 0.12 0.25 £ 0.008–1 –a – clinically significant bacterial isolates collected in Meropenem 0.03 0.12 £ 0.008–0.25 100.0 – Cefepime £ 0.06 0.12 £ 0.06–1 100.0 – 2003, specific activity profiles demonstrated that Ceftriaxone £ 0.008 £ 0.008 £ 0.008–2 100.0 – Ampicillin > 4 > 4 1 to > 4 0.0 100.0 doripenem consistently displayed the greatest Ciprofloxacin £ 0.12 £ 0.12 £ 0.12 to > 16 99.7 – ⁄ potencies (MIC90s 0.03–0.5 mg L) against Gram- Levofloxacin £ 0.03 £ 0.03 £ 0.03–0.06 100.0 – Trimethoprim– £ 0.5 > 4 £ 0.5 to > 4 75.6 22.4 positive pathogens, including oxacillin-suscept- sulphamethoxazole Clarithromycin 8 16 £ 0.25 to > 32 80.9 2.3 ible staphylococci, Strep. pneumoniae and Tetracycline £ 2 £ 2 £ 2 to > 16 94.5 5.3 b-haemolytic and viridans group streptococci, M. catarrhalis (108) Doripenem 0.016 0.03 £ 0.008–0.5 –a – compared with other carbapenems and compara- Meropenem £ 0.008 £ 0.008 £ 0.008–0.12 – – tor agents. Only oxacillin-resistant staphylococci Cefepime 0.5 1 £ 0.06–4 – – Ceftriaxone 0.12 0.5 £ 0.008–1 – – and enterococci (primarily Ent. faecium) had high- Penicillin 4 > 4 £ 0.03 to > 4 – 95.3b Ciprofloxacin £ 0.12 £ 0.12 £ 0.12–0.25 – – er MICs, thereby compromising the usefulness of Levofloxacin £ 0.03 0.06 £ 0.03–0.12 – – doripenem against these organisms. Among Trimethoprim– £ 0.5 £ 0.5 £ 0.5–2 – – sulphamethoxazole Enterobacteriaceae, the MIC50s and MIC90s Clarithromycin £ 0.25 £ 0.25 £ 0.25 – – ⁄ Tetracycline £ 2 £ 2 £ 2–16 – – of doripenem were 0.03–0.12 mg L and 0.03– 0.5 mg ⁄ L, respectively, and were similar to those aNo breakpoints have been established by the NCCLS [20]. bPercentage of isolates that are b-lactamase-positive. of meropenem (0.016–0.06 and 0.03–0.12 mg ⁄ L), whereas those of imipenem were higher (£ 0.5– 2mg⁄ L and 0.5–4 mg ⁄ L). Importantly, potencies cephalosporins. Meropenem had the lowest for all selected agents, with the exception of the £ ⁄ MIC50 ⁄ 90 ( 0.008 mg L) against M. catarrhalis. carbapenems (only two-fold increases in MIC90s), were reduced markedly for confirmed ESBL- producing E. coli and Klebsiella spp., demonstra- DISCUSSION ting the inherent stability of the carbapenem class Doripenem is a novel broad-spectrum parenteral against these enzymes. With the exception of Sten. carbapenem that is currently in the late stages of maltophilia, against which carbapenems are inac- clinical development in the USA. The microbio- tive, doripenem retains the activity profile of logical and pharmacokinetic ⁄ pharmacodynamic meropenem against P. aeruginosa, and that of features of doripenem have been described pre- imipenem against Acinetobacter spp., thereby pro- viously [10,15,16], and clinical success in early viding evidence of enhanced stability to the human trials has been reported from Japan common resistance mechanisms found in these [21–23]. Several recent studies have shown that species [13,14]. Doripenem was uniformly active doripenem incorporates the most favourable against the respiratory pathogens H. influenzae characteristics of the carbapenem class of antimi- and M. catarrhalis, with no MIC > 2 mg ⁄ L. crobial agents by combining the superior in-vitro Carbapenem agents were first described in activities of imipenem against Gram-positive 1976, with the Food and Drug Administration cocci and of meropenem against Gram-negative (FDA)-approved introductions of imipenem and pathogens. In a study of drug-resistant pathogens, meropenem occurring in 1985 and 1996, respect-

2005 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 11, 974–984 982 Clinical Microbiology and Infection, Volume 11 Number 12, December 2005 ively. These events marked a milestone in the levofloxacin and ceftriaxone. The carbapenems treatment of infections caused by fermentative are unique among b-lactams in that they have and non-fermentative Gram-negative bacilli, molecular characteristics that provide enhanced following the rise and dramatic increase in stability to the most commonly occurring b- organisms expressing b-lactamase enzymes (both lactamases. While sporadic resistance can emerge chromosomal and plasmid-mediated), which following downregulation of outer-membrane rendered ineffective many of the penicillins and porins, increased expression of efflux pumps cephalosporins (including extended-spectrum and hyperproduction of cephalosporinases, it is agents) that remain in common usage [3]. the genetic mobilisation of MBLs that gives As a class, carbapenems are innately stable to greatest cause for concern, given the high hydro- most b-lactamases of Ambler classes A, C and D, lytic activity of these enzymes and their tendency and are used widely for treating serious infections for rapid horizontal spread to other groups such involving resistant Enterobacteriaceae (including as the Enterobacteriaceae [13,14,25,33,34]. ESBL-producing and AmpC-overproducing iso- The in-vitro results in the present study lates), anaerobes, P. aeruginosa and Acinetobacter confirm, among a very large global population spp. Only recently have b-lactamases appeared of contemporary clinical isolates, earlier reports that are variably able to hydrolyse carbapenem that doripenem has a very broad spectrum of agents, including—most importantly—enzymes activity, with compromised activity limited to in Ambler class B (metallo-b-lactamases (MBLs): the oxacillin-resistant staphylococci, Ent. faecium IMP, VIM, SPM, GIM series), and also class A and Sten. maltophilia. While activity was retained (SPE, NMC-A, IMI-1, KPC) and class D (OXA against most P. aeruginosa, Acinetobacter spp. and series) enzymes [24–26]. Although the appearance some B. cepacia isolates, and while carbapenems of these enzymes has limited the usefulness of remain among the most active agents, the carbapenems in certain areas, serious problems emergence of enzyme-mediated resistance have been primarily clonal in nature, as focal remains worrying and will only be addressed outbreaks, rather than being widespread in occur- specifically by the continued development of rence, as has been reported for other b-lactamases, new agents such as doripenem. The solution including ESBLs and cephalosporinases. How- involves educational efforts targeting prescri- ever, this situation has been gradually changing bing patterns, strict application of infection with the established presence of MBLs in areas control practices, and use of data from surveil- such as Japan, South America and Italy [27–29], lance programmes for tracking resistance phe- with 6.5% of all P. aeruginosa isolates found to notypes at the local, regional and national express MBLs in Italy [29,30]. Also, plasmid- levels. mediated mobilisation of the genes encoding MBLs has resulted in their appearance in Entero- ACKNOWLEDGEMENTS bacteriaceae in a number of locations, thereby complicating further the utilisation of carbapen- We thank K. L. Meyer and P. Rhomberg for their assistance in ems [31–33]. performing this study and in preparation of the manuscript. This study was sponsored by an educational ⁄ research grant These worrying developments highlight the from Peninsula Pharmaceuticals, Inc. critical need for broad-spectrum agents that will have a high probability of success with empirical regimens, but occur at a time when pharmaceu- REFERENCES tical development of agents targeting Gram-neg- 1. Bush K. The impact of b-lactamases on the development of ative bacilli is extremely limited. Carbapenems novel antimicrobial agents. Curr Opin Infect Drugs 2002; 3: are assuming an ever greater role in institutions, 1284–1290. particularly with patient populations in whom 2. Livermore DM, Sefton AM, Scott GM. Properties and potential of ertapenem. J Antimicrob Chemother 2003; 52: isolates with multidrug resistance to commonly 331–344. used antimicrobial agents currently exist or may 3. Bonfiglio G, Russo G, Nicoletti G. Recent developments in be expected to appear. Another worrying devel- carbapenems. Expert Opin Invest Drugs 2002; 11: 529–544. opment, confirmed in the present study, is the 4. Iso Y, Irie T, Iwaki T et al. Synthesis and modification of a novel 1 b-methyl carbapenem antibiotic, S-4661. J Antibiot increasing number of Enterobacteriaceae with 1996; 49: 478–484. resistance to widely prescribed agents, such as

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