Conclusions: Doripenem appears to be a potent carbapenem with a spectrum resembling currently marketed antipseudomonal carbapenems, but with greater activity when tested against some non-fermentative bacillary strains. Continued evaluation of doripenem against isolates resistant to other ß-lactams appears to be warranted.
Keywords: resistance , broad-spectrum , ß-lactams , MBC , susceptibility testing
Introduction
Doripenem (formerly S-4661, Shionogi Co., Ltd. Japan) is a novel, broad-spectrum parenteral carbapenem antimicrobial with initial research reports dating from international meetings in 1994.1–7 The chemical formula for doripenem is (+)-(4R,5S,6S)-6-[(1R)-1-1hydroxyethyl]-4-methyl-7-oxo-3[[3S,5S)-S-(sulfamoylaminomethyl) pyrrolidin-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate (Figure 1). This structure confers ß-lactamase stability and resistance to inactivation by renal dehydropeptidases. Information from presented in vitro studies indicates that doripenem has a spectrum and potency against Gram-positive cocci most similar to imipenem or ertapenem,8–13 and a Gram-negative activity most like meropenem (two- or four-fold superior to imipenem).14
The long-recognized problems of emerging resistances among Gram-positive species15 have been complicated by dissemination of multidrug-resistant (MDR) Gram-negative organisms, some refractory to carbapenem therapy.16,17 Carbapenem development continues to discover agents with greater potency or improved pharmacokinetic properties,8 and stability to various enzymes such as metallo-ß-lactamases (L1 enzyme characteristic within Stenotrophomonas maltophilia) that can hydrolyse carbapenem compounds.
In this report, we summarize the results of testing doripenem and selected comparators against contemporary, wild-type isolates (2001–2002) worldwide. Over 900 strains were tested by reference dilution methods described by the National Committee for Clinical Laboratory Standards (NCCLS)18 and the categorical interpretations of MIC results were made using NCCLS document criteria.19
Material and Methods
Bacteria tested
A total of 902 recent clinical isolates were tested from patients with documented infections in hospitals located in the Americas and Europe. The distribution of species and strain counts was as follows: Enterobacteriaceae (281 strains); Acinetobacter baumannii (33 strains); Pseudomonas aeruginosa (35 strains); S. maltophilia (36 strains; 30.6% resistant to trimethoprim/sulfamethoxazole) other non-fermentative Gram-negative bacilli (22 strains); Haemophilus influenzae (61 strains; 28 ampicillin-resistant); Moraxella catarrhalis (33 strains; 76% penicillin-resistant); oxacillin-susceptible staphylococci (39 strains); Enterococcus spp. (84 strains; all E. faecium tested were carbapenem-resistant); streptococci (163 strains; three species groups); anaerobes (98 strains); and other Gram-positive cocci (17 strains).
Unless specified, the isolates were contemporary wild-type populations of the specified species, not enriched with resistant organisms. Identifications were determined in at least two laboratories by routine procedures utilized by those institutions.
Susceptibility testing
Doripenem reagent standard powder was supplied by Peninsula Pharmaceuticals, Inc. (Alameda, CA, USA). Comparison agents were purchased from Sigma Chemical Co. (St. Louis, MO, USA) or were provided by their domestic manufacturers (ertapenem and imipenem from Merck; meropenem from AstraZeneca; cefepime from Bristol-Myers Squibb; clavulanic acid from GlaxoSmithKline; and piperacillin/tazobactam from Wyeth).
All susceptibility tests were carried out by the reference NCCLS methods18 and interpretation of MIC values was by criteria published in NCCLS M100-S13.19 Disc diffusion tests20 with 5, 10 and 20- µg concentrations of doripenem prepared by the investigators were compared against ertapenem (10 µg), imipenem (10 µg) and meropenem (10 µg) commercially prepared (BD Microbiologic Systems, Cockeysville, MD, USA) control discs to determine the optimal disc drug content. A total of 10 wild-type and NCCLS19 quality control strains were used to determine the doripenem disc concentration. Supplements to the media were applied as specified in the NCCLS18–20 procedures to maximize growth for fastidious species such as the streptococci and H. influenzae. The anaerobes were tested by the NCCLS21 agar dilution method on Brucella blood agar.
Escherichia coli and Klebsiella spp. strains conforming to the phenotype for an extended-spectrum ß-lactamase (ESBL; MIC of 2 mg/L for aztreonam, cefotaxime, ceftazidime or ceftriaxone) were confirmed by the Etest ESBL strip (AB Biodisk, Solna, Sweden).22 Also to avoid over-representing various resistance phenotypes (example ESBLs), clustered antimicrobial-resistant strains appearing in an institution in a close interval (time), ward or service, were subjected to molecular epidemiological study by pulsed-field gel electrophoresis or automated ribotyping.23 Only a single strain from proven clusters was entered into the study, if appropriate.
Quality control was provided by the concurrent testing of strains recommended by the NCCLS19 such as E. coli ATCC 25922 and 35218, Staphylococcus aureus ATCC 25923 and 29213, Enterococcus faecalis ATCC 29212, P. aeruginosa ATCC 27853, H. influenzae ATCC 49247 and 49766, Streptococcus pneumoniae ATCC 49619, Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741. All recorded control results were within published ranges for comparison agents.19
Minimum bactericidal tests were carried out by methods described earlier11 and published by the NCCLS.24,25 Killing curves for doripenem were carried out on 10 organisms including NCCLS19 quality control strains. Concentrations of doripenem at 2x, 4x and 8x MIC were used, monitored at baseline (T0) and at 2 (T2), 4 (T4) and 8 (T8) h.
The reference MIC results for doripenem determined by broth microdilution and agar dilution were directly compared for 100 selected strains,26 with ertapenem used as a carbapenem-class control.
Tentative interpretations of the doripenem MIC results were made using the criteria of susceptible at 4 mg/L and resistant at 16 mg/L.
These breakpoints conform to those widely used for imipenem and meropenem19 and recommended by Bhavnani et al.27 using pharmacokinetic/pharmacodynamic target attainment calculations via Monte Carlo simulations for drug dosing schedules projected for the Phase II and III doripenem clinical trials.
Results and discussion
Activity against Enterobacteriaceae
Table 1 shows the activity of doripenem and six broad-spectrum ß-lactam comparison agents tested against 281 strains of Enterobacteriaceae without ESBL production. Against E. coli (31 strains), nearly all strains had a doripenem MIC of 0.015 mg/L. Imipenem was at least 16-fold less potent than doripenem. Doripenem potency against Klebsiella spp. (46 strains) was comparable to ertapenem and meropenem, but generally two- to four-fold superior to imipenem. The 23 P. mirabilis strains were slightly less susceptible to doripenem, however, the highest MIC was only 0.12 mg/L. Ertapenem and meropenem were more active, with doripenem being 16-fold more potent than imipenem (MIC90, 2 mg/L). Citrobacter spp. (29 strains) were 100.0% susceptible to doripenem. Imipenem among the carbapenems was least active (MIC90, 1 mg/L) against the citrobacters. Similarly, against two species of Enterobacter, doripenem and meropenem were the most active overall. S. marcescens MIC results showed that doripenem, ertapenem and meropenem were the most active agents with MIC90 values of 0.12 mg/L and 100.0% susceptibility rates; 16-fold more potent than imipenem. Indole-positive Proteae (four species; 39 strains) were most susceptible to ertapenem (MIC90, 0.03 mg/L) > meropenem (0.12) > doripenem (0.25) > cefepime (0.5) > imipenem (2). Only the four carbapenems, piperacillin/tazobactam and aztreonam (data not shown) inhibited all wild-type indole-positive Proteae isolates at concentrations defining susceptibility by NCCLS standards.19
Among the carbapenems, ertapenem and meropenem were most active against the Salmonella spp. followed by doripenem (MIC90, 0.06 mg/L) and imipenem (MIC90, 0.25 mg/L). The highest MIC for the Shigella spp. versus the carbapenems was 0.25 mg/L (imipenem), but the highest for doripenem was only 0.06 mg/L. Five more species of Enterobacteriaceae were tested (nine strains; see Table 1 footnote), and quite different patterns of susceptibility were observed. All carbapenems, however, were effective in vitro, but the MIC50 results varied from 0.03 mg/L (ertapenem) to 0.25 mg/L (imipenem).
Activity against non-fermentative Gram-negative bacilli
Table 2 illustrates the doripenem activity against A. baumannii (33 strains) compared to six ß-lactams. Only doripenem (75.8% inhibited at 4 mg/L), imipenem and meropenem were active against these wild-type isolates. Overall, doripenem and imipenem were the most potent agents (MIC50, 0.5 mg/L) and inhibited strains at potentially achievable breakpoint concentrations. Wild-type P. aeruginosa (Table 2) were consistently more susceptible than the Acinetobacter spp. in contemporary practice samples. Ertapenem among the tested carbapenems was not active (MIC90, >32 mg/L) and doripenem was two- and four-fold more potent than meropenem and imipenem against P. aeruginosa, respectively. Cefepime among the cephalosporins had the lowest resistance rate (0.0%; ceftazidime at 4.2%) and 8.3% of P. aeruginosa were resistant to piperacillin/tazobactam.
Doripenem, other tested carbapenems, levofloxacin and trimethoprim/sulfamethoxazole (data not shown) were the only drugs with susceptibility rates of greater than 80% when testing the remaining Gram-negative non-fermentative species (17 strains). A small number of S. (formerly Xanthomonas) maltophilia strains (36; data not shown) were very resistant to tested agents and particularly refractory to carbapenems (97.2–100.0% resistance). Eleven of these strains (30.6%) were resistant to the ‘drug-of-choice’ (trimethoprim/sulfamethoxazole).
Activity against fastidious respiratory tract pathogens
Doripenem was tested against H. influenzae (61 strains) and M. catarrhalis (33 strains) compared to ertapenem, two ß-lactam/ß-lactamase inhibitor combinations and three parenteral cephalosporins (Table 2). Doripenem MIC results were essentially equal for both groups of H. influenzae (ß-lactamase-positive and -negative by nitrocefin test), demonstrating no adverse effect of the TEM-like enzyme on its activity. Ertapenem was four-fold more active than doripenem. The doripenem MIC results tested against M. catarrhalis are also found in Table 2, and all antimicrobials except ampicillin (also penicillin, data not shown) showed an excellent spectrum and potency. ß-Lactamase production (detected by the chromogenic cephalosporin test) was noted for 25 strains (75.8%).
Activity against Gram-positive organisms
Table 3 lists the activity of doripenem and selected comparison agents tested against oxacillin-susceptible S. aureus (MIC, 2 mg/L; 20 strains). Doripenem was equal to the most potent agent (imipenem; MIC90, 0.06 mg/L) for the dilution ranges utilized. Doripenem was 128-fold more active than ceftazidime and 32-fold more potent than cefepime against these staphylococci. Among the other tested carbapenems, doripenem (MIC90, 0.06 mg/L) was four-fold more active than ertapenem (MIC90, 0.25 mg/L). Doripenem was equally potent against oxacillin-susceptible (MIC, 0.5 mg/L) coagulase-negative staphylococci isolates (MIC90, 0.06 mg/L), as that demonstrated for S. aureus. Ertapenem was generally eight-fold less active than doripenem.
E. faecalis (45 strains including six vancomycin-resistant [VRE] isolates) susceptibility testing results for doripenem showed that all of the VRE strains were resistant to doripenem at MIC values of 8 mg/L (Table 3). Doripenem was four-fold less active than imipenem, but four-fold more potent than ertapenem. Only 2.2% of E. faecalis were ampicillin-resistant and one isolate was linezolid-resistant (MIC, 8 mg/L), but susceptible to doripenem. Tests with E. faecium (29 strains, 20 VRE; data not shown) showed that none of the carbapenems displayed activity (MIC90, 8 mg/L) against this species. Ten strains of ‘other enterococci’ were also tested (Table 3) and these strains included four different species and single isolates of E. durans and E. gallinarum that had elevated doripenem MIC results (>32 mg/L). Doripenem and imipenem were four-fold more active than ertapenem against these more rarely encountered enterococci.
Doripenem MIC results for S. pneumoniae strains were grouped by their susceptibility category to penicillin [susceptible (0.06 mg/L), intermediate (0.12–1 mg/L), resistant (2 mg/L); see Table 3]. The doripenem MIC values increased as the penicillin MIC increased with MIC90 results at 0.015, 0.25 and 1 mg/L for penicillin-susceptible, -intermediate, and -resistant category pneumococcal strains, respectively. Similar increases were also noted for ertapenem, imipenem, other tested ß-lactams as well as unlisted antimicrobials such as the macrolides, chloramphenicol, tetracyclines and trimethoprim/sulfamethoxazole. Doripenem was the most active carbapenem or ß-lactam tested against the penicillin-resistant S. pneumoniae (23 strains using the tentative breakpoint of 4 mg/L).
Against viridans group streptococci (49 strains; Table 3) indexed by their susceptibility to penicillin (0.12 mg/L), doripenem activity was adversely affected by elevated penicillin MIC values (similar to S. pneumoniae). The doripenem MIC90 results increased from 0.06 to 0.5 to 4 mg/L for the penicillin-susceptible (0.12 mg/L), -intermediate (0.25–2 mg/L), and -resistant (4 mg/L) strains. Doripenem showed similar activity when compared to imipenem versus all viridans group streptococci, but exhibited a two- to four-fold greater activity than ertapenem. Ertapenem at breakpoints approved by the NCCLS19 was only effective against 7.7% of penicillin-resistant viridans group streptococci. Doripenem exhibited a potency equal to those of penicillin, clindamycin and imipenem (all at 0.06 mg/L for MIC90 results) against ß-haemolytic streptococci. For the Bacillus spp. (eight strains), doripenem was very active with an MIC50 of only 0.03 mg/L. The remaining nine isolates were Aerococcus spp. (three species, three strains), Gemella morbillorum (two strains),Lactococcus spp. (one strain), Leuconostoc spp. (two strains) and Stomatococcus mucilaginosis (one strain). Doripenem was not active versus the Leuconostoc spp. isolates (MIC, 8 mg/L).
Activity against strict anaerobic bacteria
Table 4 shows the MIC results of doripenem and four selected agents tested against six groups of strict anaerobes (98 strains). All carbapenems tested were active against this population of anaerobes with only ertapenem having non-susceptible values (MIC, 8 mg/L) for single strains of Fusobacterium spp. and Clostridium difficile. Metronidazole susceptibility rates varied from 7.1% (other Gram-positive species) to 100.0%. Clindamycin activity and potency versus the Gram-negative species was quite compromised (MIC90, >16 mg/L).
Determinations of bactericidal activity
Ten strains including eight NCCLS19 quality control organisms were tested to compare doripenem MIC and MBC results. The doripenem MBC values ranged from two- to eight-fold greater than the measured MIC with a median result of four-fold higher. Kill curves were also carried out using doripenem concentrations at 2x, 4x and 8x the measured organism MIC. Bactericidal results for doripenem were generally observed at 4x and 8x MIC for the S. aureus, E. faecalis, S. pneumoniae (Figure 2), E. coli and K. pneumoniae isolates. Occasional regrowth at 24 h to subvisible levels was noted and only to the initial inoculum level for the in 2x or 4x MIC tests (P. aeruginosa; Figure 3) possibly due to drug inactivation via induced AmpC expression.
Preliminary determinations of in vitro testing parameters
Table 5 lists the disc diffusion zones of inhibition around doripenem discs containing 5, 10, or 20 µg of drug. These tests were carried out in replicate (three discs of each concentration/strain) with two technologist observers (six doripenem results with averages shown in Table 5). Linear increases in the zone diameter were observed for doripenem discs as the disc concentration increased, progressing from a millimetre zone range of 15.3–33.8 mm for the 5 µg disc to 21.8–39.5 mm for the 20 µg disc. The 10 µg doripenem disc performed similarly to the same content discs for other control carbapenems (Table 5) when compared to their corresponding MIC values. The 10 µg disc could be recommended as a doripenem diagnostic test reagent, conforming to those concentrations used for the carbapenem class.
A comparison of agar dilution and broth microdilution MIC test results was carried out using 106 strains (NCCLS M23-A2 criteria, 100 strains) and ertapenem as a control carbapenem agent (Figure 4). Nearly 60% of values were identical by both methods. However, a slight trend toward a one log2 higher MIC by the broth-based method was observed. A total of 99.1% of doripenem MIC results were within ±one log2 dilution by both NCCLS methods.20 Ertapenem comparisons showed equality between methods, but a lower percentage (97.2%) of results within±one log2 dilution step. These results for both carbapenems were considered to be within acceptable levels of intermethod variation.26
Conclusions
This in vitro evaluation studied doripenem, a novel parenteral carbapenem,1,4 against recently isolated strains from a worldwide organism collection. Earlier reports of the microbiology features of doripenem can be summarized as follows: 1) bactericidal action;3,7,28,29 2) high affinity for PBP targets that are species-specific (PBP3 in P. aeruginosa; PBPs1, 2 and 4 in S. aureus; PBP2 in E. coli);30 3) a post-antibiotic effect of 1.8 (in vitro) to 4.3 (in vivo) h for P. aeruginosa;28,31 4) influx in Gram-negative species by OprD channels with efflux sensitivity via the MexAB-OprM system;32 5) pharmacokinetic parameters resembling meropenem with a T1/2 of approximately 1 h;6 6) low serum protein binding at 8–9%;6,7 7) low risk of convulsive side effects secondary to weak inhibition of GABA receptors;2 8) stability to a wide variety of ß-lactamases;3,7 9) success within in vivo animal models;28,29 10) endotoxin release comparable to other carbapenem class agents;29 11) high-level stability to human recombinant dehydropeptidase-I;5 12) synergy with glycopeptides when tested against oxacillin-resistant S. aureus;33 and 13) clinical success from the early human trials in Japan.34,35
The doripenem spectrum of activity was previously presented in a limited number of publications appearing between 1998 and 2002.3,4,7,8 In those studies, the strains used were collected from Japan and the susceptibility methods used were not NCCLS assays. The consensus MIC90 results for key pathogens were: oxacillin-susceptible S. aureus (0.06 mg/L) or CoNS (0.06–12.5 mg/L), oxacillin-resistant staphylococci (>32 mg/L), E. faecalis (4–16 mg/L), E. faecium (>32 mg/L), S. pneumoniae (0.008–0.5 mg/L; varies with penicillin susceptibility), serogroup A and B streptococci (0.004–0.03 mg/mL), Enterobacteriaceae (0.12–0.5 mg/L), P. aeruginosa (2–16 mg/L), Acinetobacter spp. (4 mg/L), M. catarrhalis (0.03 mg/L), H. influenzae (0.5 mg/L), anaerobes (0.12–1 mg/L) and Burkholderia cepacia complex or S. maltophilia (8–>128 mg/L). These in vitro results from early development trials clearly place doripenem as a very broad-spectrum ß-lactam only having a compromised spectrum when used alone33 against oxacillin-resistant staphylococci, E. faecium, some Burkholderia spp. and S. maltophilia, i.e. a spectrum most similar to imipenem or meropenem,8,14 but markedly superior to ertapenem.9–13 These features for doripenem were confirmed in the study reported here, where the new carbapenem was four- to 32-fold more active than imipenem against wild-type strains of Enterobacteriaceae (MIC range, 0.015–0.5, median MIC, 0.06 mg/L). Furthermore, doripenem exhibited potency and/or spectrum advantages compared with both imipenem and meropenem against the entire group of non-fermentative Gram-negative bacilli tested.
These findings have been enhanced by the early pharmacokinetic and pharmacodynamic study results27,36,37 that show doripenem to have a pharmacodynamic target producing efficacy like that of other ß-lactams (%T > MIC), dosages (short or prolonged) that can be adjusted to treat organisms (MICs at 8 mg/L) previously refractory to carbapenem therapy, and a Phase I safety/pharmacokinetic study that confirms earlier Japanese investigation results for doses up to 1000 mg every 8 h.6 These recent pharmacodynamic investigations also validated the tentative breakpoint for doripenem susceptibility at 4 mg/L used in this presentation for doses projected for the Phase 3 clinical trials.27
As resistance among key nosocomial pathogens increases,15–17 the need for broad-spectrum agents becomes critical to initial patient care or the selection of empirical regimens. The carbapenems will need to assume a greater therapeutic role, especially in those institutions and patient populations where multidrug-resistant strains have become prevalent. However, the potential exists for some metallo-ß-lactamases that can actively destroy carbapenem compounds to be more widely disseminated.16,17 Surveillance programmes and prudent prescibing practice should screen multidrug-resistant isolates for this resistance mechanism at the regional, national and local level. Only with this type of epidemiological effort will the carbapenems and new, promising compounds like doripenem be able to maintain their wide spectrum of activity and potential clinical utility.
Ackowledgements
The co-authors wish to thank the following individuals for their assistance in manuscript preparation and review: K.L. Meyer, M.L. Beach and P. Rhomberg. This study was funded by an educational/research grant from Peninsula Pharmaceuticals, Inc.
Footnotes
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; Email: ronald-jones@jmilabs.com
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