Antimicrobial activity of doripenem (S-4661): a global surveillance report (2003)

Authors


Corresponding author and reprint requests: T. R. Fritsche, JMI Laboratories, Inc., 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA
E-mail: thomas-fritsche@jmilabs.com

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 β-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 β-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 β-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 ≤ 0.5/2 mg/L, respectively). Doripenem was slightly more potent (MIC50 2 mg/L) than ertapenem and imipenem (MIC50 4 mg/L), and had a potency similar to that of meropenem (MIC50 2 mg/L), against Burkholderia cepacia (20 isolates). Both Haemophilus influenzae (1824 isolates) and Moraxella catarrhalis (108 isolates), including β-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 β-lactamase stability when compared with some carbapenems used currently to treat nosocomial infections.

Introduction

β-Lactams are among the most widely prescribed antimicrobial agents in both the community and hospital settings. Their use for over 60 years has, however, resulted in a dramatic increase in the selection of β-lactamase variants that now threaten the utility of the majority of this large drug family. Enzymes have been described that have potent hydrolytic activity against penicillins, cephalosporins (including extended-spectrum agents), cephamycins and β-lactam–inhibitor combinations [1]. The development and approval of carbapenems was a milestone in addressing this situation, because of their broad spectrum of activity against most Gram-positive and -negative pathogens, and their enhanced stability to most Ambler class A, C and D β-lactamases [2]. These agents have generally been reserved for the most severe infections, or for infections caused by organisms known to be resistant to other available β-lactams, especially those with an extended spectrum of activity (third- and fourth-generation cephalosporins).

Given the current emphasis on broad-spectrum agents targeting Gram-positive organisms, there is a paucity of agents in development that are directed at Gram-negative infections and that have the universal success and broad safety profiles enjoyed by β-lactams. In the USA, imipenem and meropenem are the only carbapenems available that display a broad spectrum of activity against the important Gram-positive bacteria, Enterobacteriaceae, anaerobes and non-fermentative bacilli such as Pseudomonas aeruginosa and Acinetobacter spp. [3].

Doripenem (formerly S-4661; Shionogi Co. Ltd, Osaka, Japan) is a novel parenteral 1-β-methyl carbapenem with a molecular structure that confers β-lactamase stability and resistance to inactivation by renal dehydropeptidases [4–7]. In-vitro studies have documented those characteristics that make doripenem unique, including a spectrum and potency against Gram-positive cocci which is most similar to that of imipenem, and an activity against Gram-negative bacteria which is most like that of meropenem (i.e., two- to four-fold greater than that of imipenem) [8–12]. A particular feature, attributed to the side chain at position 2, is greater activity against non-fermentative Gram-negative bacilli that are multidrug-resistant [13,14]. Unfortunately, none of the carbapenems is stable to the L1 enzyme produced by Stenotrophomonas maltophilia. Doripenem displays favourable pharmacokinetic, pharmacodynamic and toxicological features, similar to those of meropenem, and this promising compound is currently in phase 3 clinical trials [15–17].

Previous in-vitro studies have focused on limited populations of targeted species, particularly resistant subsets or isolates from specific anatomical sites of infection, and have not presented a large geographical sampling of contemporary isolates [8–11,18]. The present report summarises the results of testing doripenem and comparator agents against 16 008 Gram-positive and Gram-negative isolates collected as part of an international surveillance programme during 2003.

Materials and methods

Bacterial isolates tested

Non-duplicate, consecutive clinical isolates were submitted from more than 70 medical centres located in North America (38.3% of isolates), South America (13.7%) and Europe (48.0%) as part of the global surveillance programme for the year 2003. The isolates were predominantly from patients with documented bloodstream (61.9%), respiratory tract (15.5%), skin and soft tissue (7.1%) or urinary tract (9.6%) infections, and were of either nosocomial or community-acquired origin. The distribution of species and number of isolates were as follows: Enterobacteriaceae, 6240 isolates; P. aeruginosa, 829; Acinetobacter spp., 155; Sten. maltophilia, 80; Burkholderia cepacia, 20; Aeromonas spp., 44; Haemophilus influenzae, 1853; Moraxella catarrhalis, 108; Staphylococcus spp., 3711; Enterococcus spp., 1474; streptococci, 1435 (four groups); and other Gram-positive bacteria, 59. All isolates were included as submitted by the study participants and, with the single exception of vancomycin-resistant enterococci, were not enriched with resistant isolates. Participants were asked to submit additional isolates of vancomycin-resistant enterococci (142 isolates received) to better define the resistance profiles that occur within this group. Species identifications were performed by the submitting laboratories, with confirmation by the central coordinating laboratory (JMI Laboratories, North Liberty, IA, USA), using established biochemical algorithms, including the Vitek microbial identification system (bioMérieux, Hazelwood, MO, USA).

Antimicrobial susceptibility testing

All isolates were tested by the NCCLS reference broth microdilution method [19] in Mueller–Hinton broth (with the addition of lysed horse blood 2–5% v/v or Haemophilus Test Medium for testing fastidious species) against a variety of antimicrobial agents representing the most common classes and examples of drugs used in the empirical or directed treatment of the indicated pathogen. Dry-form microdilution panels and broth reagents were purchased from Trek Diagnostics (Cleveland, OH, USA). Doripenem standard powder was provided by Peninsula Pharmaceuticals (New Brunswick, NJ, USA); other agents were acquired from their respective manufacturers or were purchased from Sigma Chemical Co. (St Louis, MO, USA). Interpretation of quantitative MICs was in accordance with NCCLS criteria [20]. Enterobacteriaceae with elevated MICs (≥ 2 mg/L) for ceftazidime and/or ceftriaxone and/or aztreonam were considered to have extended-spectrum β-lactamase (ESBL)-producing phenotypes according to NCCLS criteria [20]. ESBL confirmation was by the disk approximation method, incorporating testing with and without clavulanic acid. Quality control isolates included Escherichia coli ATCC 25922 and ATCC 35218, P. aeruginosa ATCC 27853, H. influenzae ATCC 49247. Staphylococcus aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619 and Enterococcus faecalis ATCC 29212 [20].

Results

Staphylococci, streptococci and enterococci

The activities of doripenem and ten comparison agents against methicillin (oxacillin)-susceptible S. aureus and coagulase-negative staphylococci are shown in Table 1. Doripenem was the most potent agent for the dilution ranges utilised compared with the other agents, including carbapenems, and was 32- to 64-fold more potent than cefepime. Among the carbapenems tested, doripenem (MIC90 0.06 mg/L) was two-fold more active than meropenem (MIC90 0.12 mg/L) and two- to eight-fold more active than ertapenem (MIC90 0.25–0.5 mg/L) against the staphylococci. Results with isolates from different geographical regions showed minimal differences, although coagulase-negative staphylococci of Latin American origin tended to display greater resistance to ertapenem, while North American isolates were more resistant to levofloxacin (data not shown). As expected, all β-lactams displayed higher MIC values for oxacillin-resistant staphylococci (oxacillin-resistant staphylococci are considered resistant to all β-lactams), as did levofloxacin. Only vancomycin remained active against all isolates.

Table 1.  In-vitro activity of doripenem in comparison with selected antimicrobial agents against Gram-positive organisms
Organism/antimicrobial agent (no. tested)MIC (mg/L) % susceptible% resistant
50%90%Range
  • a No breakpoints have been established by the NCCLS [20].

  • b Susceptibility is predicted by the ampicillin result [20].

  • c

    One strain with G2576U mutation.

  • d Non-meningitis breakpoints are not established [20].

  • e Based upon non-meningitis breakpoints [20].

  • f

    Includes Strep. mitis (33 isolates), Strep. anginosus (14), Strep. sanguis (10), Strep. oralis (nine), Strep. constellatus (eight), Strep. milleri (seven), Strep. salivarius (seven) and others (52).

Staphylococcus aureus, oxacillin-susceptible (2705)
 Doripenem0.060.06≤ 0.008–4a
 Ertapenem0.120.25≤ 0.06 to > 8> 99.90.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5–4100.00.0
 Meropenem0.120.120.016–4100.00.0
 Cefepime24≤ 0.12 to > 1699.00.5
 Ceftriaxone440.5 to > 3298.90.3
 Ceftazidime816≤ 1 to > 1689.21.2
 Oxacillin0.51≤ 0.06–2100.00.0
 Piperacillin–tazobactam12≤ 0.12–6499.80.2
 Levofloxacin0.120.5≤ 0.03 to > 494.24.1
 Vancomycin11≤ 0.12–4100.00.0
Coagulase-negative staphylococci, oxacillin-susceptible (297)
 Doripenem0.030.06≤ 0.008–8a
 Ertapenem0.250.5≤ 0.06 to > 899.30.3
 Imipenem≤ 0.5≤ 0.5≤ 0.5–1100.00.0
 Meropenem0.120.120.016–899.70.0
 Cefepime12≤ 0.12–8100.00.0
 Ceftriaxone24≤ 0.25–3298.30.0
 Ceftazidime48≤ 1 to > 1696.30.7
 Oxacillin0.120.25≤ 0.06–0.25100.00.0
 Piperacillin–tazobactam0.251≤ 0.12–4100.00.0
 Levofloxacin0.2520.06 to > 490.95.1
 Vancomycin120.25–4100.00.0
Enterococcus faecalis (1206) and other non-faecium species (70)
 Doripenem48≤ 0.008 to > 16a
 Ertapenem8> 8≤ 0.06 to > 8
 Imipenem14≤ 0.5 to > 8
 Meropenem816≤ 0.008 to > 16
 Ceftriaxone> 32> 32≤ 0.25 to > 32
 Ampicillin24≤ 1 to > 1697.62.4
 Piperacillin–tazobactam416≤ 0.12 to > 256bb
 Levofloxacin1> 40.12 to > 461.137.6
 Vancomycin120.25 to > 1692.95.5
 Teicoplanin≤ 2≤ 2≤ 2 to > 1696.53.1
 Linezolid220.25 to > 899.90.1c
Enterococcus faecium (198)
 Doripenem> 16> 160.03 to > 16a
 Ertapenem> 8> 88 to > 8
 Imipenem> 8> 81 to > 8
 Meropenem> 16> 164 to > 16
 Ampicillin> 16> 16≤ 1 to > 168.690.4
 Ceftriaxone> 32> 320.5 to > 32
 Piperacillin–tazobactam> 256> 2568 to > 256bb
 Levofloxacin> 4> 41 to > 47.187.3
 Vancomycin> 16> 160.5 to > 1628.470.6
 Teicoplanin> 16> 16≤ 2 to > 1634.057.4
 Linezolid221–899.01.0
Streptococcus pneumoniae (885)
 Doripenem0.0160.5≤ 0.008–1a
 Ertapenem≤ 0.060.5≤ 0.06 to > 8dd
 Imipenem≤ 0.5≤ 0.5≤ 0.5–1dd
 Meropenem0.0160.5≤ 0.008–2dd
 Cefepime≤ 0.121≤ 0.12–494.9e0.5e
 Ceftriaxone≤ 0.251≤ 0.25–897.5e0.8e
 Penicillin≤ 0.032≤ 0.03 to > 467.916.1
 Piperacillin–tazobactam≤ 0.124≤ 0.12–16
 Levofloxacin120.06 to > 499.90.1
 Vancomycin0.250.5≤ 0.06–1100.0
 Erythromycin≤ 0.2516≤ 0.25 to > 3273.825.5
Viridans group streptococcif (140)
 Doripenem0.030.5≤ 0.008 to > 16a
 Ertapenem0.121≤ 0.06–4
 Imipenem≤ 0.5≤ 0.5≤ 0.5–4
 Meropenem0.060.5≤ 0.008 to > 1690.7
 Cefepime0.251≤ 0.12–890.71.4
 Ceftriaxone≤ 0.251≤ 0.25–890.72.9
 Penicillin0.062≤ 0.016–3265.77.9
 Piperacillin–tazobactam0.254≤ 0.12 to > 256
 Levofloxacin120.06 to > 499.30.7
 Vancomycin0.51≤ 0.12–299.3
 Erythromycin≤ 0.064≤ 0.06 to > 855.040.0
β-Haemolytic streptococci (397)
 Doripenem≤ 0.0080.03≤ 0.008–0.25a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06–1100.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5–1
 Meropenem≤ 0.0080.06≤ 0.008–0.5100.0
 Cefepime≤ 0.12≤ 0.12≤ 0.12–1699.5
 Ceftriaxone≤ 0.25≤ 0.25≤ 0.25–1699.2
 Penicillin≤ 0.0160.06≤ 0.016–199.7
 Piperacillin–tazobactam≤ 0.120.5≤ 0.12–4
 Levofloxacin0.51≤ 0.03–2100.00.0
 Vancomycin0.250.5≤ 0.12–1100.00.0

Susceptibility testing results for Ent. faecalis and non-faecium species revealed a small number of isolates that were resistant to vancomycin (vancomycin-resistant enterococci) and teicoplanin, occurring most commonly among North American isolates (8.2% and 4.0%, respectively). Doripenem was two-fold less active than imipenem, but two-fold more potent than ertapenem or meropenem, against these enterococci (Table 1). Only 0.9% of Ent. faecalis isolates were found to be ampicillin-resistant. One isolate from North America was linezolid-resistant (MIC > 8 mg/L) because of a G2576U mutation, and the greatest proportion (46.1%) of levofloxacin-resistant isolates was found on that continent. A majority (70.6%) of Ent. faecium isolates demonstrated resistance to vancomycin, because of the inclusion of 142 additional resistant isolates in the study. None of the carbapenems displayed significant activity (MIC90 ≥ 16 mg/L) against this species, regardless of vancomycin susceptibility patterns. The most active antimicrobial agent among those tested against Ent. faecium was linezolid (99.0% susceptible).

The population of Strep. pneumoniae tested included 32.1% of isolates that were non-susceptible to penicillin, and 25.5% that were resistant to erythromycin; the carbapenems and vancomycin were the most active agents tested (MIC90s ≤ 0.5 mg/L). Resistance to some agents varied significantly according to geographical region, with penicillin and erythromycin resistance varying from 14.1% and 15.1% in Latin America to 19.9% and 31.2%, respectively, in North America (data not shown). All isolates (100%) and 99.9% of isolates were susceptible to vancomycin and levofloxacin, respectively.

Against viridans group streptococci, doripenem (MIC50 0.03 mg/L) was two-fold more active than meropenem, and four-fold more active than ertapenem (Table 1). There were 7.9% penicillin-resistant isolates, with smaller percentages also being resistant to ceftriaxone (2.9%) and cefepime (1.4%). Penicillin resistance was greatest in Latin America (23.1%) and least in Europe (6.0%), whereas erythromycin resistance was greatest in Europe (44.8%) and least in Latin America (23.1%; data not shown). Streptococcus bovis (13 isolates) had an antibiogram most similar to that of viridans group streptococci, although the carbapenems, particularly doripenem and meropenem, displayed greater potency (MIC for all strains ≤ 0.016 mg/L). The Strep. bovis isolates were also susceptible to penicillin.

Doripenem exhibited activity (MIC50 ≤ 0.008 mg/L) equal to or greater to that of penicillin and the other carbapenems for the dilution ranges tested against β-haemolytic streptococci (groups A, B, C, F and G). All agents with established breakpoints displayed > 99% susceptibility rates, with ertapenem, meropenem, levofloxacin and vancomycin showing 100% susceptibility.

Other Gram-positive species

Doripenem was slightly less active against Micrococcus spp. (13 isolates) than against staphylococci (MIC50/90s 0.06 and 0.12 mg/L, respectively), and was similar in potency to meropenem. Only vancomycin among the selected agents was uniformly active in vitro against Corynebacterium spp. (17 isolates; MIC range 0.25–1 mg/L); all carbapenems had high MIC90 values (≥ 16 mg/L). Bacillus spp. (12 isolates) were more susceptible to doripenem (MIC50/90 0.06/4 mg/L), which was two- to four-fold more potent than the other carbapenems. Only levofloxacin and vancomycin among selected comparators were consistently more active. Doripenem and meropenem were equally active (MIC50/90s 0.12 and 0.25 mg/L) against Listeria spp. (17 isolates), and were more active than penicillin, levofloxacin and vancomycin (MIC90s 0.5, 1 and 1 mg/L, respectively).

Enterobacteriaceae

The spectrum and activity of doripenem and comparator agents against Enterobacteriaceae are listed in Table 2. Almost 50% of the E. coli isolates were ampicillin-resistant, and c. 13% were resistant to levofloxacin (10.2% in North America, 22.6% in Latin America, and 11.9% in Europe). However, > 99.9% of isolates remained susceptible to the carbapenems. Isolates from Europe had a similar antibiogram to those from the USA, whereas those from Latin America were more resistant to ampicillin, third-generation cephalosporins and fluoroquinolones (data not shown). In total, 121 isolates of E. coli were confirmed as ESBL producers by the clavulanate inhibition test (4.0% of the total E. coli collection tested). The prevalence of ESBL-producing E. coli in North America, Latin America and Europe was 1.5%, 8.9% and 4.6%, respectively. Potencies of all selected agents, including fluoroquinolones, were decreased markedly among ESBL producers, with the exception of the carbapenems. Doripenem displayed a potency against the ESBL producers (MIC90 0.06 mg/L) that was one dilution higher than that against the wild-type population (MIC90 0.03 mg/L).

Table 2.  In-vitro activity of doripenem in comparison with selected antimicrobial agents against contemporary wild-type isolates of Enterobacteriaceae
Organism/antimicrobial agent (no. tested)MIC (mg/L) % susceptible% resistant
50%90%Range
  1. a No breakpoints have been established by the NCCLS [20].

  2. b Percentages in parentheses indicate those isolates meeting the NCCLS screening criteria (MIC  ≥ 2 mg/L) for an ESBL-producing isolate [20].

Escherichia coli (3023)
 Doripenem0.030.03≤ 0.008–1a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06–499.90.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5 to > 8> 99.9< 0.1
 Meropenem0.0160.03≤ 0.008–2100.00.0
 Cefepime≤ 0.12≤ 0.12≤ 0.12 to > 1697.62.0
 Ceftriaxone≤ 0.25≤ 0.25≤ 0.25 to > 3296.53.0 (4.5)b
 Ceftazidime≤ 1≤ 1≤ 1 to > 1697.21.7 (5.1)b
 Ampicillin8> 16≤ 1 to > 1650.248.6
 Ampicillin–sulbactam4> 32≤ 0.25 to > 3256.425.3
 Piperacillin–tazobactam24≤ 0.12 to > 25697.31.4
 Levofloxacin≤ 0.03> 4≤ 0.03 to > 485.612.6
E. coli (ESBL-confirmed; 121)
 Doripenem0.030.060.016–1a
 Ertapenem≤ 0.060.25≤ 0.06–499.10.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5100.00.0
 Meropenem0.030.060.016–2100.00.0
 Cefepime16> 16≤ 0.12 to > 1643.047.9
 Ceftriaxone> 32> 32≤ 0.25 to > 3224.870.2
 Ceftazidime16> 16≤ 1 to > 1647.132.2
 Ampicillin> 16> 1616 to > 160.099.2
 Ampicillin–sulbactam32> 322 to > 324.188.4
 Piperacillin–tazobactam81280.5 to > 25680.213.2
 Levofloxacin> 4> 4≤ 0.03 to > 434.761.2
Klebsiella spp. (1107)
 Doripenem0.030.060.016 to > 16a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06 to > 898.80.8
 Imipenem≤ 0.5≤ 0.5≤ 0.5 to > 899.70.3
 Meropenem0.030.03≤ 0.008 to > 1699.60.2
 Cefepime≤ 0.124≤ 0.12 to > 1692.36.1
 Ceftriaxone≤ 0.2532≤ 0.25 to > 3285.59.8 (16.9)b
 Ceftazidime≤ 116≤ 1–1689.38.6 (15.9)b
 Ampicillin> 16> 16≤ 1 to > 165.678.0
 Ampicillin–sulbactam8> 32≤ 0.25 to > 3270.522.4
 Piperacillin–tazobactam232≤ 0.12 to > 25688.28.6
 Levofloxacin0.062≤ 0.03 to > 490.87.1
Klebsiella spp. (ESBL-confirmed; 155)
 Doripenem0.060.120.016–8a
 Ertapenem≤ 0.060.5≤ 0.06 to > 897.91.4
 Imipenem≤ 0.5≤ 0.5≤ 0.5–2100.00.0
 Meropenem0.030.120.016–2100.00.0
 Cefepime8> 16≤ 0.12 to > 1654.235.5
 Ceftriaxone> 32> 32≤ 0.25 to > 3211.660.6
 Ceftazidime> 16> 16≤ 1 to > 1636.851.6
 Ampicillin> 16> 16> 160.0100.0
 Ampicillin–sulbactam> 32> 320.5 to > 325.285.8
 Piperacillin–tazobactam8> 2560.25 to > 25660.031.0
 Levofloxacin0.5> 4≤ 0.03 to > 465.228.4
Enterobacter spp. (601)
 Doripenem0.060.12≤ 0.008–4a
 Ertapenem≤ 0.061≤ 0.06 to > 896.81.3
 Imipenem≤ 0.51≤ 0.5 to > 899.70.2
 Meropenem0.030.12≤ 0.008–899.80.4
 Cefepime≤ 0.124≤ 0.12 to > 1695.73.2
 Ceftriaxone≤ 0.25> 32≤ 0.25 to > 3277.514.7
 Ceftazidime≤ 1> 16≤ 1 to > 1676.020.5
 Ampicillin> 16> 162 to > 165.388.0
 Ampicillin–sulbactam32> 321 to > 3222.056.8
 Piperacillin–tazobactam264≤ 0.12 to > 25681.48.7
 Levofloxacin0.06> 4≤ 0.03 to > 487.510.5
Citrobacter spp. (136)
 Doripenem0.030.06≤ 0.008–2a
 Ertapenem≤ 0.060.12≤ 0.06–499.20.0
 Imipenem≤ 0.51≤ 0.5 to > 899.30.7
 Meropenem0.030.06≤ 0.008–4100.00.0
 Cefepime≤ 0.121≤ 0.12 to > 1697.82.2
 Ceftriaxone≤ 0.2516≤ 0.25 to > 3287.54.4
 Ceftazidime≤ 1> 16≤ 1 to > 1688.211.0
 Ampicillin> 16> 162 to > 1610.377.2
 Ampicillin–sulbactam8> 322 to > 3264.023.5
 Piperacillin–tazobactam2320.5 to > 25688.24.4
 Levofloxacin≤ 0.032≤ 0.03 to > 491.26.6
Proteus mirabilis (307)
 Doripenem0.120.250.016–0.5a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06–499.60.0
 Imipenem12≤ 0.5–899.70.0
 Meropenem0.060.060.016–1100.00.0
 Cefepime≤ 0.12≤ 0.12≤ 0.12 to > 1698.01.6
 Ceftriaxone≤ 0.25≤ 0.25≤ 0.25 to > 3296.71.6
 Ceftazidime≤ 1≤ 1≤ 1 to > 1698.40.7
 Ampicillin2> 16≤ 1 to > 1671.326.7
 Ampicillin–sulbactam1320.5 to > 3284.710.1
 Piperacillin–tazobactam0.251≤ 0.12–6498.40.0
 Levofloxacin0.06> 4≤ 0.03 to > 486.010.1
Indole-positive Proteae (148)
 Doripenem0.120.50.03–1a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06–0.12100.00.0
 Imipenem24≤ 0.5–4100.00.0
 Meropenem0.060.120.016–0.5100.00.0
 Cefepime≤ 0.120.25≤ 0.12 to > 1699.30.7
 Ceftriaxone≤ 0.252≤ 0.25 to > 3297.30.7
 Ceftazidime≤ 14≤ 1 to > 1694.61.4
 Ampicillin> 16> 16≤ 1 to > 168.187.2
 Ampicillin–sulbactam16320.5 to > 3230.431.1
 Piperacillin–tazobactam0.54≤ 0.12–6499.30.0
 Levofloxacin0.064≤ 0.03 to > 486.59.5
Serratia spp. (187)
 Doripenem0.120.250.03–1a
 Ertapenem≤ 0.060.12≤ 0.06–0.5100.00.0
 Imipenem≤ 0.51≤ 0.5–899.50.0
 Meropenem0.030.060.016–0.25100.00.0
 Cefepime≤ 0.120.5≤ 0.12 to > 1695.74.3
 Ceftriaxone≤ 0.2516≤ 0.25 to > 3289.85.4
 Ceftazidime≤ 1≤ 1≤ 1 to > 1694.63.8
 Ampicillin> 16> 164 to > 164.388.7
 Ampicillin–sulbactam32> 324 to > 327.574.7
 Piperacillin–tazobactam2320.5 to > 25689.81.6
 Levofloxacin0.121≤ 0.03 to > 493.53.8
Salmonella spp. (530)
 Doripenem0.060.060.016–0.25a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06–0.12100.00.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5–2100.00.0
 Meropenem0.030.030.016–0.5100.00.0
 Cefepime≤ 0.12≤ 0.12≤ 0.12 to > 1697.40.6
 Ceftriaxone≤ 0.25≤ 0.25≤ 0.25 to > 3296.63.0
 Ceftazidime≤ 1≤ 1≤ 1 to > 1699.40.4
 Ampicillin2> 16≤ 1 to > 1675.823.4
 Ampicillin–sulbactam232≤ 0.25 to > 3280.615.7
 Piperacillin–tazobactam440.5 to > 25696.03.6
 Levofloxacin0.060.25≤ 0.03–499.80.0
Shigella spp. (161)
 Doripenem0.030.060.016–0.06a
 Ertapenem≤ 0.06≤ 0.06≤ 0.06100.00.0
 Imipenem≤ 0.5≤ 0.5≤ 0.5100.00.0
 Meropenem0.030.030.016–0.03100.00.0
 Cefepime0.250.5≤ 0.12–1100.00.0
 Ceftriaxone≤ 0.25≤ 0.25≤ 0.25–1100.00.0
 Ceftazidime≤ 1≤ 1≤ 1100.00.0
 Ampicillin> 16> 16≤ 1 to > 1622.477.6
 Ampicillin–sulbactam32321 to > 3222.452.2
 Piperacillin–tazobactam240.25–8100.00.0
 Levofloxacin≤ 0.03≤ 0.03≤ 0.03–1100.00.0

Against Klebsiella spp., the potency of doripenem was comparable to that of meropenem and the other carbapenems, given the dilution schedules utilised, with ≥ 98.8% of isolates being susceptible. Geographical differences in the Klebsiella spp. antibiogram (decreased activity against third-generation cephalosporins) were caused primarily by the presence of confirmed ESBL-producing isolates, which comprised 14% of isolates overall, and which were most prevalent in Latin America (28.6%), followed by Europe (15.6%) and North America (6.9%). The doripenem MIC50/90s for ESBL-confirmed isolates were both only two-fold higher than those for the entire population; however, the MIC90 of ertapenem was eight-fold higher, while that of imipenem remained essentially unchanged. The inhibitor combinations ampicillin–sulbactam and piperacillin–tazobactam had markedly reduced activity for the ESBL subset, as did levofloxacin (Table 2).

Enterobacter spp. were susceptible to carbapenems, with doripenem and meropenem having an identical MIC90 (0.12 mg/L), making them eight-fold more active than either ertapenem or imipenem. Third- and fourth-generation cephalosporins, piperacillin–tazobactam and levofloxacin all showed varying degrees of activity against Enterobacter spp. (76.0–95.7% susceptibility). Likewise, doripenem and meropenem were the most active compounds (MIC50/90s 0.03/0.06 mg/L) against Citrobacter spp. (136 isolates). Among the carbapenems, imipenem was least active (MIC90 1 mg/L), although 99.3% of isolates remained susceptible. Cefepime and levofloxacin were the next most active agents tested (97.8% and 91.2% susceptible; Table 2).

The MIC90 of doripenem for Proteus mirabilis was slightly higher than that of meropenem (MIC90s 0.25 and 0.06 mg/L, respectively); however, the highest doripenem MIC was only 0.5 mg/L, compared with 1 mg/L for meropenem. Ertapenem was slightly more active (MIC90 ≤ 0.06 mg/L), although the range extended to 4 mg/L. Rates of resistance to ampicillin (26.7%), ampicillin–sulbactam (10.1%) and levofloxacin (10.1%) were elevated. Piperacillin–tazobactam was similar in activity to the carbapenems (98.4% susceptible). The agents demonstrating greatest activity against indole-positive Proteae (four species), in decreasing order by MIC90s, were: ertapenem (≤ 0.06 mg/L) > meropenem (0.12 mg/L) > cefepime (0.25 mg/L) > doripenem (0.5 mg/L) > imipenem = ceftazidime = piperacillin–tazobactam = levofloxacin (4 mg/L).

Against Serratia spp., doripenem, ertapenem and meropenem were the most active agents tested, with MIC90s of 0.25, 0.12 and 0.06 mg/L, respectively, and ≥ 99.5% susceptibility rates. Cefepime, ceftazidime and levofloxacin also demonstrated > 90% susceptibility among the selected comparators. Salmonella spp. were > 95% susceptible to all selected agents, with the exceptions of ampicillin (75.8%) and ampicillin–sulbactam (80.6%). Most Shigella spp. were resistant to ampicillin (77.6%) and ampicillin–sulbactam (52.2%), but were otherwise susceptible to all other selected agents. The highest doripenem MIC for the Salmonella and Shigella spp. was 0.06 mg/L (Table 2).

Non-fermentative Gram-negative bacilli and Aeromonas spp.

Doripenem was the most active agent (MIC90 8 mg/L) among the carbapenems against wild-type P. aeruginosa(Table 3), being slightly more potent than meropenem (MIC90 16 mg/L), imipenem and ertapenem (MIC90 > 8 mg/L). Resistance in P. aeruginosa to all tested carbapenems was lowest in North America (2–6%), intermediate in Europe (8–15%) and highest in Latin America (10–21%), based upon proposed tentative breakpoints for doripenem, which are identical to those of other carbapenems (Table 4). The greatest resistance to other agents was observed for ceftriaxone (75.8%), levofloxacin (27.5%), aztreonam (21.7%), tobramycin (21.5%), ceftazidime (19.2%) and piperacillin–tazobactam (18.2%).

Table 3.  In-vitro activity of doripenem in comparison with selected antimicrobial agents against isolates of non-fermentative Gram-negative bacilli and Aeromonas spp.
Organism/antimicrobial agent (no. tested)MIC (mg/L) % susceptible% resistant
50%90%Range
  1. a No breakpoints have been established by the NCCLS [20].

Pseudomonas aeruginosa (829)
 Doripenem0.580.03 to > 16a
 Ertapenem8> 80.12 to > 8
 Imipenem1> 8≤ 0.5 to > 880.713.5
 Meropenem0.5160.016 to > 1683.511.7
 Cefepime4> 16≤ 0.12 to > 1676.611.6
 Ceftriaxone> 32> 320.5 to > 327.275.8
 Ceftazidime4> 16≤ 1 to > 1675.019.2
 Piperacillin–tazobactam8256≤ 0.12 to > 25681.818.2
 Aztreonam8> 160.25 to > 1664.321.7
 Levofloxacin0.5> 40.06 to > 469.027.5
 Tobramycin0.5> 16≤ 0.12 to > 1677.321.5
Acinetobacter spp. (155)
 Doripenem0.540.016 to > 16a
 Ertapenem4> 8≤ 0.06 to > 8
 Imipenem≤ 0.52≤ 0.5 to > 892.37.1
 Meropenem18≤ 0.016 to > 1689.77.7
 Cefepime8> 16≤ 0.12 to > 1657.429.7
 Ceftriaxone32> 32≤ 0.25 to > 3231.040.6
 Ceftazidime8> 16≤ 1 to > 1652.337.1
 Piperacillin–tazobactam32> 256≤ 0.12 to > 25649.743.9
 Aztreonam> 16> 16≤ 0.12 to > 169.074.2
 Levofloxacin0.5> 4≤ 0.03 to > 457.438.1
 Tobramycin1> 16≤ 0.12 to > 1667.726.5
Burkholderia cepacia (20)
 Doripenem280.12 to > 16a
 Ertapenem48≤ 0.06 to > 8
 Imipenem48≤ 0.5 to > 865.010.0
 Meropenem240.06 to > 1690.010.0
 Cefepime816≤ 0.12 to > 1685.010.0
 Ceftriaxone16> 32≤ 0.25 to > 3235.020.0
 Ceftazidime44≤ 1 to > 1690.010.0
 Piperacillin–tazobactam42560.5 to > 25680.015.0
 Aztreonam16> 16≤ 0.12 to > 1640.020.0
 Levofloxacin14≤ 0.3 to > 480.010.0
 Tobramycin> 16> 16≤ 0.12 to > 1615.075.0
Stenotrophomonas maltophilia (80)
 Doripenem> 16> 161 to > 16a
 Ertapenem> 8> 81 to > 8
 Imipenem> 8> 82 to > 81.398.7
 Meropenem> 16> 160.5 to > 165.183.5
 Cefepime16> 161 to > 1621.342.5
 Ceftriaxone> 32> 322 to > 322.591.2
 Ceftazidime8> 16≤ 1 to > 1656.335.0
 Piperacillin–tazobactam256> 2568 to > 2565.056.2
 Aztreonam> 16> 164 to > 163.891.2
 Levofloxacin140.12 to > 487.53.7
 Tobramycin> 16> 161 to > 1611.372.5
Aeromonas spp. (44)
 Doripenem0.510.03–4a
 Ertapenem0.251≤ 0.06 to > 8
 Imipenem≤ 0.52≤ 0.5 to > 893.22.3
 Meropenem0.1210.016–497.70.0
 Cefepime≤ 0.120.25≤ 0.12–4100.00.0
 Ceftriaxone≤ 0.251≤ 0.25–3297.70.0
 Ceftazidime≤ 1≤ 1≤ 1 to > 1697.72.3
 Piperacillin–tazobactam81281–25660.511.6
 Aztreonam≤ 0.120.25≤ 0.12–2100.00.0
 Levofloxacin≤ 0.030.25≤ 0.03 to > 497.72.3
 Tobramycin140.25 to > 1693.26.8
Table 4.  Cumulative percentage of Pseudomonas aeruginosa isolates from different geographical regions susceptible to each carbapenem concentration
Region/antimicrobial agent (no. isolates)Cumulative % of isolates susceptible to each conc. (mg/L)
≤ 0.51248≥ 16
North America (226)
 Doripenem6987929698100
 Meropenem6684909396100
 Imipenem1569899194100
Europe (450)
 Doripenem5373798692100
 Meropenem5468758388100
 Imipenem1159748085100
Latin America (153)
 Doripenem4459657690100
 Meropenem4256637179100
 Imipenem1151656779100

Imipenem was the most active carbapenem (MIC50/90 ≤ 0.5/2 mg/L) tested against Acinetobacter spp. (Table 3). Doripenem (MIC50/90 0.5/4 mg/L) and meropenem (MIC50/90 1/8 mg/L) were also active against these wild-type isolates, whereas ertapenem displayed marginal activity (MIC50/90 4/> 8 mg/L). Among other agents tested, tobramycin was the most active compound (MIC50 1 mg/L; 67.7% susceptible), with cefepime (MIC50 8 mg/L; 57.4% susceptible), levofloxacin (MIC50 0.5 mg/L; 57.4% susceptible) and piperacillin–tazobactam (MIC50 32 mg/L; 49.7% susceptible) also retaining some activity. As with P. aeruginosa, Latin American isolates of Acinetobacter spp. tended to display much greater resistance to all drug classes, especially tobramycin (data not shown).

Among other Gram-negative bacilli investigated, B. cepacia isolates were variable in their patterns of susceptibility to carbapenems, with meropenem being most active (MIC50/90 2/4 mg/L; 90.0% susceptible), followed by doripenem (MIC50/90 2/8 mg/L) and imipenem (MIC50/90 4/8 mg/L; 65.0% susceptible). Ceftazidime and cefepime were also active (90% and 85% of isolates susceptible), followed by piperacillin–tazobactam and levofloxacin (both showing 80% susceptibility). Resistance was most pronounced with tobramycin (75%), aztreonam (20%) and ceftriaxone (20%). Sten. maltophilia isolates were very resistant to the agents tested, particularly carbapenems (83.5–98.7% resistant). Levofloxacin (87.5% susceptible) was the most active agent, followed by ceftazidime (56.3%).

Aeromonas spp. were generally susceptible (> 93.0%) to all agents tested, except for piperacillin–tazobactam (60.5%). All carbapenems had similar activity (MIC90 1–2 mg/L) against Aeromonas spp.

Fastidious respiratory tract pathogens

Meropenem was slightly more active than doripenem (MIC50/90s 0.03/0.12 and 0.06/0.25 mg/L, respectively) against H. influenzae (both β-lactamase-positive and -negative phenotypes; Table 5). The adverse effects of the TEM enzyme in β-lactamase-positive isolates on the activity of the carbapenems was minimal. The β-lactamase-positive rate among H. influenzae isolates was 21.8%, but the number of β-lactamase-negative ampicillin-resistant isolates was only 0.1%(Table 5). All other agents tested also exhibited potent activity (> 94% susceptibility) against H. influenzae, with the exceptions of trimethoprim–sulphamethoxazole (75.6–83.5%) and clarithromycin (80.9–86.7%). Against M. catarrhalis, doripenem and the comparators tested showed potent activity, with the expected exception of penicillin. β-Lactamase production was demonstrated for all but five (95.3%) of the isolates with a chromogenic cephalosporin test. Doripenem was more potent (MIC50/90 ≤ 0.016/0.03 mg/L) than the fluoroquinolones (ciprofloxacin and levofloxacin), and showed superior activity when compared with the cephalosporins. Meropenem had the lowest MIC50/90 (≤ 0.008 mg/L) against M. catarrhalis.

Table 5.  In-vitro activity of doripenem in comparison with selected antimicrobial agents against isolates of Haemophilus influenzae and Moraxella catarrhalis
Organism/antimicrobial agent (no. tested)MIC (mg/L) % susceptible% resistant
50%90%Range
  • a No breakpoints have been established by the NCCLS [20].

  • b

    Percentage of isolates that are

  • β

    β-lactamase-positive.

H. influenzae, β-lactamase- negative (1426)
 Doripenem0.060.25≤ 0.008–2a
 Meropenem0.030.12≤ 0.008–0.25100.0
 Cefepime≤ 0.060.12≤ 0.06 to > 899.8
 Ceftriaxone≤ 0.0080.016≤ 0.008 to > 1699.9
 Ampicillin≤ 0.51≤ 0.5 to > 499.60.1
 Ciprofloxacin≤ 0.12≤ 0.12≤ 0.12 to > 1699.9
 Levofloxacin≤ 0.03≤ 0.03≤ 0.03–0.12100.0
 Trimethoprim– sulphamethoxazole≤ 0.5> 4≤ 0.5 to > 483.514.7
 Clarithromycin816≤ 0.25 to > 3286.71.1
 Tetracycline≤ 2≤ 2≤ 2 to > 1699.20.6
H. influenzae, β-lactamase- positive (398)
 Doripenem0.120.25≤ 0.008–1a
 Meropenem0.030.12≤ 0.008–0.25100.0
 Cefepime≤ 0.060.12≤ 0.06–1100.0
 Ceftriaxone≤ 0.008≤ 0.008≤ 0.008–2100.0
 Ampicillin> 4> 41 to > 40.0100.0
 Ciprofloxacin≤ 0.12≤ 0.12≤ 0.12 to > 1699.7
 Levofloxacin≤ 0.03≤ 0.03≤ 0.03–0.06100.0
 Trimethoprim– sulphamethoxazole≤ 0.5> 4≤ 0.5 to > 475.622.4
 Clarithromycin816≤ 0.25 to > 3280.92.3
 Tetracycline≤ 2≤ 2≤ 2 to > 1694.55.3
M. catarrhalis (108)
 Doripenem0.0160.03≤ 0.008–0.5a
 Meropenem≤ 0.008≤ 0.008≤ 0.008–0.12
 Cefepime0.51≤ 0.06–4
 Ceftriaxone0.120.5≤ 0.008–1
 Penicillin4> 4≤ 0.03 to > 495.3b
 Ciprofloxacin≤ 0.12≤ 0.12≤ 0.12–0.25
 Levofloxacin≤ 0.030.06≤ 0.03–0.12
 Trimethoprim– sulphamethoxazole≤ 0.5≤ 0.5≤ 0.5–2
 Clarithromycin≤ 0.25≤ 0.25≤ 0.25
 Tetracycline≤ 2≤ 2≤ 2–16

Discussion

Doripenem is a novel broad-spectrum parenteral carbapenem that is currently in the late stages of clinical development in the USA. The microbiological and pharmacokinetic/pharmacodynamic features of doripenem have been described previously [10,15,16], and clinical success in early human trials has been reported from Japan [21–23]. Several recent studies have shown that doripenem incorporates the most favourable characteristics of the carbapenem class of antimicrobial agents by combining the superior in-vitro activities of imipenem against Gram-positive cocci and of meropenem against Gram-negative pathogens. In a study of drug-resistant pathogens, doripenem retained the greatest potency among carbapenems against ESBL- and AmpC-producing enteric bacilli, as well as against penicillin-resistant Strep. pneumoniae[9]. Also, a greater proportion of carbapenem-resistant P. aeruginosa and Acinetobacter spp. isolates were inhibited by doripenem at ≤ 4 mg/L [7–9]. When compared with several other anti-pseudomonal agents, including other carbapenems, doripenem was associated with the lowest rate of spontaneous resistance [13].

The aim of the present study was to characterise the global antibiogram for doripenem and other agents used in similar clinical circumstances. For a large (16 008 isolates) collection of clinically significant bacterial isolates collected in 2003, specific activity profiles demonstrated that doripenem consistently displayed the greatest potencies (MIC90s 0.03–0.5 mg/L) against Gram-positive pathogens, including oxacillin-susceptible staphylococci, Strep. pneumoniae and β-haemolytic and viridans group streptococci, compared with other carbapenems and comparator agents. Only oxacillin-resistant staphylococci and enterococci (primarily Ent. faecium) had higher MICs, thereby compromising the usefulness of doripenem against these organisms. Among Enterobacteriaceae, the MIC50s and MIC90s of doripenem were 0.03–0.12 mg/L and 0.03–0.5 mg/L, respectively, and were similar to those of meropenem (0.016–0.06 and 0.03–0.12 mg/L), whereas those of imipenem were higher (≤ 0.5–2 mg/L and 0.5–4 mg/L). Importantly, potencies for all selected agents, with the exception of the carbapenems (only two-fold increases in MIC90s), were reduced markedly for confirmed ESBL-producing E. coli and Klebsiella spp., demonstrating the inherent stability of the carbapenem class against these enzymes. With the exception of Sten. maltophilia, against which carbapenems are inactive, doripenem retains the activity profile of meropenem against P. aeruginosa, and that of imipenem against Acinetobacter spp., thereby providing evidence of enhanced stability to the common resistance mechanisms found in these species [13,14]. Doripenem was uniformly active against the respiratory pathogens H. influenzae and M. catarrhalis, with no MIC > 2 mg/L.

Carbapenem agents were first described in 1976, with the Food and Drug Administration (FDA)-approved introductions of imipenem and meropenem occurring in 1985 and 1996, respectively. These events marked a milestone in the treatment of infections caused by fermentative and non-fermentative Gram-negative bacilli, following the rise and dramatic increase in organisms expressing β-lactamase enzymes (both chromosomal and plasmid-mediated), which rendered ineffective many of the penicillins and cephalosporins (including extended-spectrum agents) that remain in common usage [3].

As a class, carbapenems are innately stable to most β-lactamases of Ambler classes A, C and D, and are used widely for treating serious infections involving resistant Enterobacteriaceae (including ESBL-producing and AmpC-overproducing isolates), anaerobes, P. aeruginosa and Acinetobacter spp. Only recently have β-lactamases appeared that are variably able to hydrolyse carbapenem agents, including—most importantly—enzymes in Ambler class B (metallo-β-lactamases (MBLs): IMP, VIM, SPM, GIM series), and also class A (SPE, NMC-A, IMI-1, KPC) and class D (OXA series) enzymes [24–26]. Although the appearance of these enzymes has limited the usefulness of carbapenems in certain areas, serious problems have been primarily clonal in nature, as focal outbreaks, rather than being widespread in occurrence, as has been reported for other β-lactamases, including ESBLs and cephalosporinases. However, this situation has been gradually changing with the established presence of MBLs in areas such as Japan, South America and Italy [27–29], with 6.5% of all P. aeruginosa isolates found to express MBLs in Italy [29,30]. Also, plasmid-mediated mobilisation of the genes encoding MBLs has resulted in their appearance in Enterobacteriaceae in a number of locations, thereby complicating further the utilisation of carbapenems [31–33].

These worrying developments highlight the critical need for broad-spectrum agents that will have a high probability of success with empirical regimens, but occur at a time when pharmaceutical development of agents targeting Gram-negative bacilli is extremely limited. Carbapenems are assuming an ever greater role in institutions, particularly with patient populations in whom isolates with multidrug resistance to commonly used antimicrobial agents currently exist or may be expected to appear. Another worrying development, confirmed in the present study, is the increasing number of Enterobacteriaceae with resistance to widely prescribed agents, such as levofloxacin and ceftriaxone. The carbapenems are unique among β-lactams in that they have molecular characteristics that provide enhanced stability to the most commonly occurring β-lactamases. While sporadic resistance can emerge following downregulation of outer-membrane porins, increased expression of efflux pumps and hyperproduction of cephalosporinases, it is the genetic mobilisation of MBLs that gives greatest cause for concern, given the high hydrolytic activity of these enzymes and their tendency for rapid horizontal spread to other groups such as the Enterobacteriaceae [13,14,25,33,34].

The in-vitro results in the present study confirm, among a very large global population of contemporary clinical isolates, earlier reports that doripenem has a very broad spectrum of activity, with compromised activity limited to the oxacillin-resistant staphylococci, Ent. faecium and Sten. maltophilia. While activity was retained against most P. aeruginosa, Acinetobacter spp. and some B. cepacia isolates, and while carbapenems remain among the most active agents, the emergence of enzyme-mediated resistance remains worrying and will only be addressed specifically by the continued development of new agents such as doripenem. The solution involves educational efforts targeting prescribing patterns, strict application of infection control practices, and use of data from surveillance programmes for tracking resistance phenotypes at the local, regional and national levels.

Acknowledgements

We thank K. L. Meyer and P. Rhomberg for their assistance in performing this study and in preparation of the manuscript. This study was sponsored by an educational/research grant from Peninsula Pharmaceuticals, Inc.

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