Antimicrobial Agents and Chemotherapy, August 2004, p . 3136-3140, Vol . 48, No . 8

Doripenem is a new 1-ß-methyl carbapenem with specific side chain substitutions enhancing activity against nonfermentative gram-negative bacilli (4) . Published reports dating from 1994 describe doripenem as having the following features: (i) bactericidal action against most species; (ii) stability to human renal dehydropeptidases; (iii) ß-lactamase stability to commonly occurring enzymes, including the emerging extended-spectrum ß-lactamases (ESBLs); (iv) pharmacokinetic and pharmacodynamic qualities similar to those of meropenem (half-life of 1 h) with minimal risk of convulsive adverse reactions; (v) postantibiotic effects of nearly 2 h in vitro for P . aeruginosa; and (vi) low serum protein binding (8.9%) (1, 3, 9-11, 14-16; Y . Kimura, K . Murakami, H . Onoue, J . Shimada, and S . Kuwahara, Abstr . 34th Intersci . Conf . Antimicrob . Agents Chemother., abstr . F37, 1994; K . Inoue, Y . Hamana, S . Iyobe, and S . Mitsubashi, Abstr . 36th Intersci . Conf . Antimicrob . Agents Chemother., abstr . F112, 1996; D . A . Thye, T . Kilfoil, A . Leighton, and M . Wikler, Abstr . 43rd Intersci . Conf . Antimicrob . Agents Chemother., abstr . A-21, 2003) . In this report, we summarize the doripenem activities against a challenge collection of recent clinical isolates (394 strains) having defined resistance phenotypes or genotypes .

All quantitative MIC testing was performed by the NCCLS M7-A6 method (12) with medium supplements appropriate for each tested organism . A total of 24 antimicrobials were tested, including four carbapenems (doripenem, ertapenem, imipenem, and meropenem) . The antimicrobials were obtained from their U.S . manufacturers and dispensed into broth microdilution panels (TREK Diagnostics, Cleveland, Ohio) or into agar plates by the investigator . Doripenem was provided by Peninsula Pharmaceuticals, Inc . (Alameda, Calif.) . The quality control strains recommended by the NCCLS (13) were processed concurrently with the challenge organism collection . All control MIC results were within published NCCLS ranges (13) . Interpretation of MIC results was according to the criteria of the NCCLS M100-S13 document (13) and proposed pharmacodynamic-based breakpoints for doripenem susceptibility at 4 µg/ml (2, 5; D . R . Andes, S . Kiem, and W . A . Craig, Abstr . 43rd Intersci . Conf . Antimicrob . Agents Chemother., abstr . A-308, 2003; S . M . Bhavnani, J . P . Hammel, B . B . Cirincioni, D . Thye, and M . A . Wikler, Abstr . 43rd Intersci . Conf . Antimicrob . Agents Chemother., abstr . A-11, 2003; Thye et al., 43rd ICAAC) .

A total of 394 organisms, derived from a worldwide collection of isolates for the years 2001 and 2002, were tested . The strains were characteristic of various resistance phenotypes, and many had the genotype of the mechanism of resistance determined . Enterobacteriaceae having ESBL-mediated resistances according to NCCLS criteria (13) and supplemental Etests with three drugs (aztreonam, ceftriaxone, and ceftazidime) were selected for study (Table 1) . Among the nonfermentative gram-negative bacilli processed, carbapenem-resistant (MIC, 16 µg/ml) isolates of Acinetobacter spp . (24 strains) and P . aeruginosa (34 strains) were tested . Additional P . aeruginosa isolates (15 strains) with documented (by PCR and gene sequencing) IMP, VIM, and SPN enzymes in the metallo-ß-lactamase series were also tested . Stenotrophomonas maltophilia (36 strains), a species with the L1 ß-lactamase expressing carbapenem resistance, was also tested (Tables 1 and 2) . Other resistance subgroups were examined by MIC testing, as follows: (i) Haemophilus influenzae (15 strains) with the ß-lactamase-negative ampicillin-resistant phenotype and strains with elevated MICs of 2 µg/ml for imipenem ("imipenem resistant" [quotation marks indicate authors’ definition, not NCCLS]), (ii) Streptococcus pneumoniae strains resistant to penicillin (23 strains; MIC, 2 µg/ml) or resistant to ceftriaxone (11 strains; MIC, 4 µg/ml), (iii) viridans group streptococci resistant to penicillin (13 strains; MIC, 4 µg/ml), (iv) Corynebacterium jeikeium (10 strains), (v) Enterococcus faecium (29 strains), (vi) oxacillin-resistant Staphylococcus aureus (16 strains) and coagulase-negative staphylococci (34 strains), and (vii) carbapenem-resistant isolates of Enterobacter spp . (four strains) and Serratia marcescens (two strains; SME-1 enzyme producers) (2) .

 
Table 1 summarizes the doripenem spectrum and potency against 201 isolates of gram-negative organisms with varied ß-lactam resistance patterns . Doripenem (MIC at which 90% of the isolates were inhibited [MIC₉₀] range, 0.03 to 0.25 µg/ml) and all comparison carbapenems inhibited the ESBL-producing Enterobacteriaceae isolates at 2 µg/ml . The doripenem potency against these ESBL-producing enteric bacilli was generally equal to that of meropenem but was four- to eightfold superior to that of ertapenem (except for Proteus mirabilis) and imipenem . Other alternative classes of drugs had susceptibility rates ranging from 9.1 to 90.9%, with the best agent being cefoxitin (Table 1) . The ceftazidime-resistant strains of Citrobacter spp., Enterobacter spp., and S . marcescens were all susceptible to the carbapenems . Again, doripenem MIC₉₀s were equal to or 2-fold lower than those of meropenem, and doripenem was consistently 4- to 32-fold more active than either ertapenem or imipenem . Cefepime and amikacin were the most active noncarbapenem comparison agents (50.0 to 100.0% susceptibility) .

Carbapenem-resistant Acinetobacter spp . (MIC of 16 µg/ml for either imipenem or meropenem) were generally resistant to all tested antimicrobials (Table 1), but the lowest resistance rates were observed for amikacin (62.5%) and doripenem (50.0%) . Similarly, the carbapenem-resistant P . aeruginosa strains were usually multiply resistant, and the lowest rates of resistance were found for doripenem (29.4%) and cefepime (41.2%) . Many of the doripenem MICs (41.2%) among these P . aeruginosa strains were 8 µg/ml . Metallo-ß-lactamases collected from a worldwide collection (from Italy, Poland, Brazil, the United States, and Japan) were representative of all major groups (bla_IMP, bla_VIM, and bla_SPM) . As expected, the carbapenems were rarely active (86.7 to 100.0% resistance), and aztreonam (33.3% resistance) was the widest-spectrum agent tested .

At a susceptible breakpoint of 4 µg/ml for all active carbapenems, 20.8 and 22.4% of carbapenem-resistant Acinetobacter and P . aeruginosa (carbapenem-resistant) strains, respectively, were inhibited by doripenem .

Table 2 lists other groupings of resistance subsets (12 groups; 193 strains), with doripenem results uniquely presented . Doripenem was very active (MIC₉₀, 4 µg/ml; susceptibility of 100.0%) against ceftriaxone- and penicillin-resistant S . pneumoniae (34 strains), penicillin-resistant viridans group streptococci, ß-lactamase-negative ampicillin-resistant and "imipenem-resistant" H . influenzae, and two carbapenem-resistant S . marcescens strains . Marginal coverage by doripenem was observed for the Corynebacterium spp . (40.0% susceptibility) and for a limited number of carbapenem-resistant Enterobacter spp . (75.0% susceptibility) . As has been demonstrated for the carbapenem class, doripenem was not active against contemporary strains of oxacillin-resistant staphylococci (MIC₉₀, 16 µg/ml), E . faecium (MIC₉₀, >32 µg/ml), and S . maltophilia (MIC₉₀, >32 µg/ml) .

As the number of new agents to address antimicrobial-resistant gram-positive cocci increases, so does the rate of untreatable multidrug-resistant gram-negative bacilli . Currently available broad-spectrum agents against gram-positive organisms include older glycopeptides (vancomycin and teicoplanin), quinupristin-dalfopristin, linezolid, and daptomycin, in addition to investigational compounds such as dalbavancin, oritavancin, ramoplanin (a topical agent), and various cephalosporins that are active against oxacillin-resistant staphylococci . In contrast to the above-listed agents against gram-positive organisms, a paucity of investigational antimicrobials directed at gram-negative pathogens have reached human clinical trials in the last decade . The carbapenems have clearly become the drugs of choice for serious gram-negative infections in clinical environments where resistance has been documented; in fact, only imipenem and meropenem possess reliably broad spectrums that inhibit all significant gram-positive pathogens, Enterobacteriaceae, anaerobes, and particularly the nonfermentative gram-negative bacilli (Acinetobacter spp . and P . aeruginosa) . The last organisms have been especially problematic due to contracting multidrug resistances, unique enzyme-mediated resistances (metallo-ß-lactamases or Bush group 2f), efflux pump mutations, or outer membrane alterations (6, 7, 8) .

Doripenem, a new 1-ß-methyl carbapenem, was documented in earlier published reports to be a broad-spectrum, pseudomonas-active carbapenem with general ß-lactamase and human renal dehydropeptidase stability . Many of the doripenem antimicrobial features were the same as those of meropenem, including serum elimination half-life, postantibiotic effect against gram-negative isolates, improved safety via reduced seizure risks, and a capacity for prolonged infusions with a lower total drug requirement or a reduced number of doses per day (1, 3-5, 9-11, 14-17; Inoue et al., 36th ICAAC) . Doripenem was also noted to be more potent than meropenem against key pathogens, including many gram-positive cocci and the nonfermentative gram-negative bacilli (14-16; Inoue et al., 36th ICAAC) . These differences reduce the number of strains for which doripenem MICs are >4 µg/ml, thus expanding its potential clinical utility against strains of Acinetobacter spp . and P . aeruginosa, for which imipenem or meropenem MICs may be 8 or 16 µg/ml (Bhavnani et al., 43rd ICAAC) . Because approximately 20% of contemporary carbapenem-resistant strains may be treatable with doripenem (Table 2), this enhanced spectrum at 4 µg/ml would be valuable in clinical environments where multidrug resistances have become endemic or epidemic .

Our findings in testing doripenem against challenging antimicrobial-resistant isolates clearly demonstrate near complete activity against Enterobacteriaceae that are resistant to extended-spectrum cephalosporins by ESBL or AmpC mechanisms . This feature was secondary to excellent potency (MIC₉₀ range, 0.03 to 0.25 µg/ml) and ß-lactamase stability that contrasted to those of ertapenem when tested against the same species (5) . A wider spectrum of activity and greater potency against Acinetobacter spp . and P . aeruginosa were also confirmed for doripenem when the same susceptible and intermediate concentrations were utilized as for imipenem and meropenem . The assumption of comparable pharmacokinetics and pharmacodynamics for the three antipseudomonal carbapenems, leading to similar breakpoint concentrations, appears to be validated (15; Andes et al., 43rd ICAAC; Bhavnani et al., 43rd ICAAC) .

Other species that were resistant by various mechanisms and that remained inhibited by 4 µg of doripenem per ml were (i) the penicillin-resistant streptococci, (ii) H . influenzae with all resistance patterns tested, and (iii) many Enterobacteriaceae that were resistant to other carbapenems by outer membrane protein alterations, hyperexpression of AmpC, or acquisition of a Bush group 2f carbapenemase (2) . The last finding will require further study with more isolates having this enzyme type . In contrast, many gram-negative bacilli with altered penicillin binding proteins or carbapenemase production, the oxacillin-resistant staphylococci, E . faecium, C . jeikeium, and S . maltophilia were highly resistant to doripenem and other carbapenem agents (1, 17) .

In summary, these findings confirm the doripenem activity and spectrum against contemporary (2001 to 2002) clinical isolates worldwide . Like other carbapenems, doripenem has a very broad spectrum of activity, enabling use against infecting pathogens found to be resistant to many other classes of antimicrobials . With the potential for greater breadth of use, to include some previously carbapenem-resistant or -intermediate isolates, doripenem should be advanced to clinical trials for the therapy of serious nosocomial infections .

This study was funded by an educational/research grant from Peninsula Pharmaceuticals .

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