Activities of Doripenem (S-4661) against Drug-Resistant Clinical Pathogens

Abstract

Doripenem (formerly S-4661), a new 1-β-methyl carbapenem, was challenged with a worldwide collection of 394 drug-refractory isolates. For endemic extended-spectrum β-lactamase- and stably derepressed AmpC-producing enteric bacilli, the doripenem MICs at which 90% of the isolates were inhibited (MIC₉₀s) were 0.03 to 0.5 μg/ml, generally lower than those of comparator carbapenems. A greater proportion of strains among carbapenem-resistant nonfermentative gram-negative bacilli were inhibited by doripenem at ≤4 μg/ml, and doripenem was the most active carbapenem (MIC₉₀, 1 to 4 μg/ml) against penicillin-resistant streptococci.

Infection chemotherapy has been seriously compromised by the steadily emerging antimicrobial resistances among gram-positive and -negative nosocomial pathogens (6, 7). Because of their wide spectrum of activity, the carbapenem class of β-lactams has become an attractive treatment choice for initial empirical regimens or as a reserved therapy for defined resistant isolates. The most widely usable carbapenems possess significant activity against nonfermentative gram-negative bacilli such as Acinetobacter spp. and Pseudomonas aeruginosa, in addition to excellent potencies against gram-positive cocci (except Enterococcus faecium and oxacillin-resistant staphylococci), Enterobacteriaceae, and the strict anaerobes (1, 5, 17). Although the carbapenems remain the broadest-spectrum β-lactams, the emergence and dissemination of various carbapenemase and efflux pump mechanisms of resistance may present a future challenge to this β-lactam class (7, 8).

Doripenem is a new 1-β-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) β-lactamase stability to commonly occurring enzymes, including the emerging extended-spectrum β-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-β-lactamase series were also tested. Stenotrophomonas maltophilia (36 strains), a species with the L1 β-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 β-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.

Activities of four carbapenems and other selected comparison agents against 201 gram-negative organisms possessing various resistance mechanisms

Organism, resistance mechanism,a and antimicrobial (no. tested)	MIC (μg/ml)			%b
	50%	90%	Range	Susceptible	Resistant
E. coli, ESBL producing (29)
Doripenem	≤0.015	0.03	≤0.015-0.12	100.0	0.0
Ertapenem	0.03	0.25	≤0.015-2	100.0	0.0
Imipenem	0.12	0.5	≤0.06-0.5	100.0	0.0
Meropenem	≤0.06	≤0.06	≤0.06-0.25	100.0	0.0
Piperacillin-tazobactam	2	>64	≤0.5->64	79.3	10.3
Cefepime	4	>16	0.25->16	72.4	24.1
Ciprofloxacin	0.12	>2	≤0.03->2	58.6	41.4
Amikacin	2	>32	≤0.25->32	75.9	10.3
K. pneumoniae, ESBL producing (34)
Doripenem	0.03	0.06	≤0.015-0.25	100.0	0.0
Ertapenem	0.06	0.25	≤0.015-0.5	100.0	0.0
Imipenem	0.12	0.25	≤0.06-0.5	100.0	0.0
Meropenem	≤0.06	0.12	≤0.06-1	100.0	0.0
Piperacillin-tazobactam	16	>64	2->64	67.6	26.5
Cefepime	4	>16	0.5->16	73.5	17.6
Ciprofloxacin	≤0.03	>2	≤0.03->2	76.5	14.7
Amikacin	16	>32	1->32	73.5	14.7
P. mirabilis, ESBL producing (11)
Doripenem	0.12	0.25	0.06-0.25	100.0	0.0
Ertapenem	≤0.015	0.03	≤0.015-0.03	100.0	0.0
Imipenem	1	2	0.5-2	100.0	0.0
Meropenem	≤0.06	0.12	≤0.06-0.12	100.0	0.0
Piperacillin-tazobactam	2	16	≤0.5->64	90.9	9.1
Cefepime	16	>16	0.25->16	36.4	45.5
Ciprofloxacin	>2	>2	≤0.03->2	9.1	63.7
Amikacin	32	>32	2->32	45.5	45.5
Citrobacter spp., ceftazidime resistant (11)
Doripenem	0.03	0.06	0.03-0.12	100.0	0.0
Ertapenem	0.25	0.5	0.03-1	100.0	0.0
Imipenem	0.5	1	0.25-4	100.0	0.0
Meropenem	≤0.06	0.12	≤0.06-0.12	100.0	0.0
Piperacillin-tazobactam	32	64	4->64	18.2	9.1
Cefepime	1	2	0.5-4	100.0	0.0
Ciprofloxacin	0.5	>2	≤0.03->2	72.7	18.2
Amikacin	2	2	1-4	100.0	0.0
Enterobacter spp., ceftazidime resistant (33)
Doripenem	0.06	0.12	≤0.015-4	100.0	0.0
Ertapenem	0.5	4	≤0.015-8	87.9	9.1
Imipenem	0.25	1	0.12-8	93.9	0.0
Meropenem	0.12	0.25	≤0.06-4	100.0	0.0
Piperacillin/Tazobactam	64	>64	≤0.5->64	15.2	36.4
Cefepime	2	4	≤0.12-16	97.0	0.0
Ciprofloxacin	1	>4	≤0.03->2	57.6	39.4
Amikacin	2	>32	1->32	81.8	12.1
S. marcescens, ceftazidime resistant (10)
Doripenem	0.12	0.5	0.03-2	100.0	0.0
Ertapenem	0.12	2	0.03-8	90.0	10.0
Imipenem	0.5	1	0.12-2	100.0	0.0
Meropenem	≤0.06	0.5	≤0.06-2	100.0	0.0
Piperacillin/Tazobactam	16	>64	1->64	50.0	30.0
Cefepime	4	>16	0.25->16	50.0	30.0
Ciprofloxacin	>2	>2	0.03->2	30.0	60.0
Amikacin	16	>32	2->32	60.0	30.0
Acinetobacter spp., carbapenem resistant (24)
Doripenem	8	>32	1->32	20.8	50.0
Ertapenem	>32	>32	4->32	0.0	95.8
Imipenem	>8	>8	2->8	16.7	83.3
Meropenem	>8	>8	2->8	4.2	75.0
Piperacillin-tazobactam	>64	>64	64->64	0.0	95.8
Cefepime	>16	>16	8->16	4.2	79.2
Ciprofloxacin	>4	>4	0.5->4	8.3	87.5
Amikacin	>32	>32	2->32	25.0	62.5
P. aeruginosa
Carbapenem resistant (34)
Doripenem	8	>32	0.5->32	29.4	29.4
Ertapenem	>32	>32	8->32	0.0	100.0
Imipenem	>8	>8	8->8	0.0	91.2
Meropenem	>8	>8	0.5->8	2.9	67.6
Piperacillin-tazobactam	>64	>64	4->64	44.1	55.9
Cefepime	16	>16	2->16	29.4	41.2
Ciprofloxacin	>2	>2	0.12->2	17.6	82.4
Amikacin	>32	>32	2->32	44.1	55.9
MβL resistant (15)
Doripenem	>32	>32	4->32	6.7	86.7
Ertapenem	>32	>32	>32	0.0	100.0
Imipenem	>8	>8	8->8	0.0	93.3
Meropenem	>8	>8	8->8	0.0	93.3
Piperacillin-tazobactam	64	>64	8->64	53.3	46.7
Aztreonam	16	>16	4->16	46.7	33.3
Ciprofloxacin	>2	>2	0.06-2	20.0	73.3
Amikacin	>32	>32	2->32	26.7	53.3

^aESBL as defined by the NCCLS (13). Ceftazidime-resistant strains have stably derepressed AmpC enzyme production. Carbapenem resistance is to imipenem or meropenem at ≥16 μg/ml. MβL resistant indicates metallo-β-lactamase (IMP, VIM, or SPM)-producing strains.

^bSusceptibility criteria of the NCCLS (13), if available. The susceptibility criteria for doripenem were tentatively placed at ≤4 μg/ml for susceptible and ≥16 μg/ml for resistant.

TABLE 2.

Activity of doripenem tested by reference methods against 12 other groups of antimicrobial-resistant organisms (193 strains)

Organism (no. tested)	Resistance phenotypea	MIC (μg/ml)			%b
		50%	90%	Range	Susceptible	Resistant
Corynebacterium spp. (10)	MDR	32	>32	0.03->32	40.0	60.0
E. faecium (29)	MDR	>32	>32	0.06->32	3.4	86.2
S. aureus (16)	OR	16	16	0.25-32	0.0	100.0
Coagulase-negative staphylococci (34)	OR	0.5	16	≤0.015->32	0.0	100.0
S. pneumoniae (11)	CTX-R	0.5	1	0.5-2	100.0	0.0
S. pneumoniae (23)	PEN-R	0.5	1	0.25-2	100.0	0.0
Viridans group streptococci (13)	PEN-R	2	4	0.25-4	100.0	0.0
H. influenzae (5)	BLNAR	2		2-4	100.0	0.0
H. influenzae (10)	“IMP-R”	0.5	0.5	0.12-1	100.0	0.0
Enterobacter spp. (4)	CARB-R	4		2-16	75.0	25.0
S. marcescens (2)	CARB-Rc	0.25		0.25-4	100.0	0.0
S. maltophilia (36)	MDR	>32	>32	32->32	0.0	100.0

^aMDR, multidrug resistant, including vancomycin resistance among the enterococci; OR, oxacillin resistant; CTX-R, ceftriaxone MIC at ≥4 μg/ml; PEN-R, penicillin MIC at ≥2 μg/ml; BLNAR, β-lactamase-negative ampicillin resistant; “IMP-R,” imipenem MIC at ≥2 μg/ml; CARB-R, carbapenem MIC at ≥16 μg/ml.

^bNCCLS interpretive criteria for other carbapenems with activity against P. aeruginosa. The susceptibility criteria for doripenem were tentatively placed at ≤4 μg/ml for susceptible and ≥16 μg/ml for resistant.

^cStrains produce an SME-1, Bush group 2f β-lactamase (2).

Table 1 summarizes the doripenem spectrum and potency against 201 isolates of gram-negative organisms with varied β-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-β-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, β-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-β-lactamases or Bush group 2f), efflux pump mutations, or outer membrane alterations (6, 7, 8).

Doripenem, a new 1-β-methyl carbapenem, was documented in earlier published reports to be a broad-spectrum, pseudomonas-active carbapenem with general β-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 β-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.