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Activity of a novel carbapenem, doripenem, against anaerobic pathogens
Available online at www.sciencedirect.com
Diagnostic Microbiology and Infectious Disease 63 (2009) 447 – 454 www.elsevier.com/locate/diagmicrobio
Activity of a novel carbapenem, doripenem, against anaerobic pathogens Ellie J.C. Goldstein⁎, Diane M. Citron RM Alden Research Laboratory, Culver City, CA 90230, USA The David Geffen School of Medicine at Los Angeles, CA 90074, USA Received 23 January 2009; accepted 23 January 2009
Abstract Doripenem, a synthetic 1-β-methyl carbapenem, has a broad-spectrum of activity against almost all species of anaerobic bacteria, including all Bacteroides fragilis group species, most with MIC90 results at ≤1 μg/mL (with the exception of Sutterella wadsworthensis). Against Clostridium difficile strains, it has a narrow range of inhibitory concentrations (1–4 μg/mL) that “may be achievable in the colon”, potentially resulting in lower disease rates. It has been shown to be active in vitro against strains isolated from a variety of clinical infections, including bacteremias, diabetic foot and other soft tissues infections and in intra-abdominal and pelvic sites. In addition, a study of a pyometrium animal model of mixed infections noted a better microbiologic response than with imipenem. Two phase 3 multinational clinical trials of complicated mixed aerobic/anaerobic intra-abdominal infections noted “noninferiority” of doripenem when compared with meropenem, but in vitro against the anaerobes, it was “more potent than meropenem, ertapenem, … and similar to imipenem”. Doripenem activity against anaerobes seems comparable with the other extant carbapenems. Although resistance among anaerobic bacteria to this agent is possible, it remains relatively rare. © 2009 Elsevier Inc. All rights reserved. Keywords: Doripenem; Anaerobes; Carbapenems; Resistance
1. Introduction Doripenem is a synthetic 1-β-methyl carbapenem with a broad-spectrum of activity (Jones et al., 2004b). Its structure confers stability against dehydropeptidase-1 and many β-lactamases (Jones et al., 2004a, 2005). Most attention has been focused on doripenem aerobic Gram-positive activity that is similar to imipenem and its aerobic Gramnegative rod activity that is similar to meropenem. A few studies have reported on its in vitro anaerobic activity (Jones et al., 2004b). The gene for carbapenemase is present in some strains of Bacteroides, but it may be expressed only partially or not at all, resulting in a large range of MIC values (Edwards and Read, 2000; Hecht, 2004; Podglajen et al., 1992). In addition,) Wexler et al. (2005) have noted that efflux “is not a clinically significant resistance mechanism” for anaerobes against doripenem. Doripenem has been
⁎ Corresponding author. Santa Monica, CA 904040, USA. Tel.: +1-310315-1511; fax: +1-310-315-3663. E-mail address: [email protected] (E.J.C. Goldstein). 0732-8893/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.01.022
approved by the United States Food and Drug Administration (US-FDA) for clinical use in complicated intraabdominal infections. This manuscript reviews the extant data on doripenem's activity against anaerobic bacteria. In vitro data limited to those isolates where investigators reported on ten or more isolates are noted in Table 1. Table 2 lists the microbiologic cure rates for anaerobic organisms for which doripenem is approved by the US-FDA. 2. Results and review 2.1. Breakpoints Brown and Traczewski (2005) studied 10 ATCC reference strains, including 3 anaerobic organisms, and, based on modal MIC values observed ±1 log2 dilution, proposed tentative MIC breakpoints for doripenem of ≤1 μg/mL for streptococci and ≤2 μg/mL for all other genera. For anaerobes, they used a broth microdilution method with Brucella broth supplemented with 5% lysed horse blood, 1 mg/L of vitamin K1, and 5 mg/L of hemin. They did not recommend any quality control (QC) ranges for Eubacterium
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Table 1 In vitro activity of doripenem and other carbapenems against anaerobic bacteria Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
B. fragilis
26
Doripenem Meropenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
0.125 to 1 0.06 to 2 0.125 to 2 0.25 to N32 0.12 to N32 0.12 to N32 0.12 to N32 0.06 to 2 0.06 to 2 0.06 to 2 0.25 to 0.25 0.12 to 0.25 0.03 to 0.12 0.25 to 1 0.25 to 16 0.12 to 8 0.06 to 2 0.12 to 4 0.12 to 16 0.12 to 16 0.12/16 0.25 to 16 0.12 to 8 0.06 to 8 0.03 to 2 0.12 to 8 0.5 to 8 0.12 to 8 0.25 to 8 0.25 to 16 0.12 to 2 0.06 to 1 0.03 to 1 0.06 to 2 0.12 to 8 0.12 to 8 0.12 to 8 0.12 to 8 0.25 to 0.5 0.12 to 0.5 0.25 to 0.5 0.5 to 2 0.12 to 2 0.03 to 0.5 0.06 to 0.5 0.12 to 2 0.25 to 4 0.12 to 4 0.12 to 4 0.25 to 16 0.25 to 4 0.25 to 4 0.12 to 2 0.5 to 8 0.25 to 4 0.12 to 4 0.12 to 4 0.25 to 8 0.15 to 2 0.25 to 8 0.12 to 8 0.25 to 8
0.25/0.5 0.12/1 0.5/1 0.5/2 0.25/8 0.5/4 0.25/4 0.12/0.5 0.12/0.5 0.12/0.5 0.25/0.25 0.12/0.25 0.12/0.12 0.12/0.12 0.5/1 0.12/0.5 0.25/0.5 0.25/0.5 0.5/1 0.25/1 0.5/1 0.5/2 0.25/1 0.12/1 0.12/0.25 0.25/2 0.5/2 0.25/2 0.5/4 1/4 0.5/1 0.25/0.5 0.5/1 0.5/2 0.5/1 0.5/2 1/2 2/4 0.25/0.5 0.25/0.5 0.25/0.5 0.5/1 0.5/1 0.25/0.5 0.25/0.5 0.5/1 0.5/2 0.5/2 0.5/2 1.0/4 0.25/1 0.25/0.5 0.25/0.5 0.5/2 0.5/2 0.25/2 0.5/2 0.5/2 0.5/2 1/2 0.25/2 1/4
Jones
60
22
10
81
198
70
B. thetaiotaomicron
30
42
78
30
B. ovatus
20
78
10
Bacteroides caccae
16
Parabacteroides distasonis
15
Sourcesb
Liu
Blood
Mikamo
GYN
Goldstein
DFI
Wexler
Various
Snydman
Various
Credito
Various
Liu
Blood
Wexler
Various
Snydman
Various
Credito
Various
Wexler
Various
Snydman
Various
Credito
Various
Snydman
Various
Snydman
Various
E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454
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Table 1 (continued) Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
Sourcesb
20
Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
0.25 to 1 0.12 to 1 0.25 to 1 0.5 to 2 0.12 to 1 0.12 to 2 0.25 to 1 0.12 to 2 0.12 to 2 0.25 to 4 0.25 to 2 0.12 to 4 0.12 to 1 0.12 to 1 0.06 to 1 0.06 to 2 0.12 to 4 0.12 to 4 0.12 to 8 b0.015 to 0.12 b0.015 to 0.12 b0.015 to 0.03 0.03 to 0.5 0.06 to 0.25 0.03 to 0.25 b0.016 to 0.12 0.06 to 0.5 0.03 to 0.125 0.03 to 0.12 0.03 to 0.12 0.03 to 0.23 0.03 to 0.06 b0.015 to 0.06 b0.016 to 0.06 b0.016 to 0.12 0.06 to 0.12 b0.016 to 0.06 0.03 to 0.06 0.06 to 0.12 b0.016 to 0.03 b0.016 to 0.06 b0.016 to 0.06 b0.016 to 0.06 b0.016 to 0.25 ≤0.016 to 0.12 ≤0.016 to 0.25 ≤0.016 to 0.12 0.12 to 1 0.06 to 1 0.25 to 1 0.06/0.5 0.06 to 1 0.06 to 0.25 0.5 to 2 0.06 to 0.12 0.03 to 0.12 0.03 to .012 0.06 to 0.25 0.03 to 0.12 0.06 to 31 0.03 to N32 0.03 to 16 0.03 to 1
0.5/1 0.12/0.5 0.5/1 0.5/1 0.5/1 0.25/0.5 1/1 0.5/2 0.5/2 0.5/2 1/2 0.5/2 0.25/1 0.25/1 0.5/1 0.12/2 0.25/1 0.25/1 0.25/8 0.06/0.12 0.06/0.12 0.03/0.02 0.25/0.5 0.06/0.12 0.06/0.12 0.03/0.06 0.25/0.25 0.06/0.12 0.03/0.12 0.03/0.12 0.06/0.25 0.03/0.06 0.03/0.06 0.03/0.06 0.03/0.06 0.06/0.12 0.06/0.06 0.03/0.03 0.12/0.12 b0.016/0.03 ≤0.016/0.03 0.03/0.03 ≤0.016/0.03 b0.016/0.25 ≤0.016/0.12 ≤0.016/0.25 ≤0.016/0.12 0.25/1 1/1 1/1 0.06/0.5 0.12/0.25 0.12/0.25 1/1 0.06/0.25 0.12/0.12 0.06/0.12 012/0.25 0.12/0.12 4/8 4/4 1/4 0.5/1
Credito
Various
Snydman
Various
Snydman
Various
Credito
Various
Mikamo
GYN
Goldstein
DFI
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Wexler
Various
Wexler
Various
Bacteroides uniformis
21
B. vulgatus
31
20
P. bivia
28
14
30
P. disiens
10
P. corporis
10
P. buccae
10
F. nucleatum
20
F. necrophorum
18
F. mortiferum
10
F. varium
10
B. wadsworthia
21
S. wadsworthensis
12
(continued on next page)
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E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454
Table 1 (continued) Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
Sourcesb
C. difficile
16
Doripenem Meropenem Ertapenem Doripenem Meropenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
b0.015 to 0.25 1 to 4 4 to 8 0.5 to 4 1 to 4 1 to 4 1 to 4 4 to 8 4 to 8 b0.015 to 0.03 ≤0.015 0.03 to 0.12 0.03 to 0.12 0.06 to 0.12 0.06 to 0.12 0.25 to 4 0.06 to 0.25 ≤0.016 to 0.06 ≤0.016 to 0.03 ≤0.016 to 0.12 ≤0.016 to 0.12 0.015 to 0.5 0.015 to 0.25 0.03 to 1 ≤0.015 to 0.25 ≤0.015 to 0.5 ≤0.015 to 0.25 ≤0.015 to 1 0.06 to 0.12 0.06 to 0.25 0.12 to 0.25 0.06 to 0.12 0.06 to 0.12 0.06 to 0.12 0.03 to 0.06 0.03 to 0.06 b0.015 to 0.12 ≤0.015 to 0.12 ≤0.015 to 0.06 ≤0.015 to 1 ≤0.016 to 0.12 ≤0.016 to 0.12 ≤0.016 to 0.06 ≤0.016 to 0.5 0.12 to 2 0.25 to 2 0.06 to 2 0.25 to 2 b0.016 to 0.12 0.03 to 0.25 0.03 to 0.12 ≤0.016 to 0.25 0.03 to 0.25 0.06 to 0.5 ≤0.015 ≤0.06 to 0.5 0.06 to 0.06 0.06 to 0.06 0.06 to 0.12 0.06 to 0.06
0.03/0.06 2/2 4/4 1/2 2/2 2/4 1/4 8/8 4/8 b0.015/0.03 ≤0.015/≤0.015 0.06/0.12 0.06/0.12 0.06/0.12 0.06/0.12 0.5/0.5 0.06/0.25 0.03/0.03 ≤0.016/≤0.016 0.06/0/12 0.06/0.12 0.06/0.12 0.03/0.12 0.12/1 0.06/0.12 0.06/0.12 0.03/0.06 0.06/0.12 0.12/0.12 0.12/0.12 0.25/0.25 0.12/0.12 0.06/0.12 0.06/0.12 0.06/0.06 0.06/0.06 b0.015/0.06 ≤0.015/0.12 0.015/0.03 ≤0.015/0.25 ≤0.016/0.03 ≤0.016/0.03 ≤0.016/0.03 ≤0.016/0.06 0.25/2 0.25/2 0.06/1 0.5/2 b0.016/0.06 0.03/0.25 0.03/0.06 0.03/0.12 0.06/0.12 0.12/0.25 ≤0.015/≤0.015 0.12/0.25 0.06/0.06 0.06/0.06 0.06/0.06 0.06/0.06
Jones
Various
Hecht
Various
Credito
Various
Goldstein
DFI
Snydman
Various
Credito
Various
Mikamo
GYN
Goldstein
DFI
Snydman
Various
Credito
Various
Goldstein
DFI
Credito
Various
Credito
Various
Credito
Various
Goldstein
DFI
Snydman
Various
110 20
C. perfringens
10
13
30
F. magna
21
30
10
10
P. asaccharolyticus
20
10
P. anaerobius
10
P. micra
10
Propionibacterium acnes
14
18
a b
Breakpoints for anaerobes: doripenem, ≤1 μg/mL, and meropenem, imipenem, ertapenem, ≤4 μg/mL. DFI = diabetic foot infections; GYN = gynecologic infections.
E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454 Table 2 Microbiologic cure rates for specific pathogens isolated in complicated intraabdominal infections (Doribax® package insert) Organism
No. of strains
No./% cured
B. fragilis B. thetaiotaomicron B. caccae B. uniformis B. vulgatus Non-fragilis Bacteroides Total B. fragilis group
67 34 25 22 11 14 173
56/83.6% 30/88.2% 23/92% 19/86.4% 11/100% 13/92.9% 152 /87.9%
Breakpoint for anaerobes: doripenem, ≤1 μg/mL; imipenem, ≤4 μg/mL; meropenem, ≤4 μg/mL; ertapenem, ≤4 μg/mL.
lentum ATCC 43055 but suggested a QC range of 0.12 to 0.5 μg/mL for Bacteroides fragilis ATCC 25285 (95.5% within range) and 0.12 to 1 μg/mL for Bacteroides thetaiotaomicron ATCC 29741 (97.2% within range). Although Brown and Traczewski's (1) recommendations of QC ranges for B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 were accepted by the Antimicrobial Susceptibility Testing Subcommittee of the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee on Clinical Laboratory Standards) in the June 2004 meeting and have since been published in the M11-A7 (CLSI, 2007) document, the US-FDA accepted their proposed QC ranges but established a breakpoint of ≤1 μg/ mL for anaerobes (Doribax Package Insert, 2008). This selection of 1 μg/mL as an anaerobic organism breakpoint needs to be considered when interpreting the published literature and the authors' statements of percentage susceptibility, which have been published in that interim. The anaerobic breakpoints for meropenem, imipenem, and ertapenem remain ≤4 μg/mL. This disparity may also be reconciled soon. 2.2. Pharmacokinetics After a 1-h infusion of 500 mg of doripenem, the mean Cmax in 24 healthy volunteers was 23 μg/mL (Standard deviation, 6.6 μg/mL) and the area under the curve (AUC) was 36.3 (SD, 8.8) μg h/mL (Doribax® package insert). It penetrates into the peritoneal and retroperitoneal fluid at concentrations that exceed the anaerobic breakpoint. After a 30-min 500-mg infusion, it achieved concentrations of 9.53 to 13.9 μg/mL at 90 min and a tissue to plasma concentration ratio of 516% (311–842%) at 6.5 h (14). After a 250-mg 30-min infusion, doripenem achieved peritoneal exudate concentrations of 2.36 to 5.17 μg/mL and a tissue to plasma concentration ratio of 160% (32.2– 322%) at 4.5 h (Doribax® package insert). 2.3. In vitro susceptibility studies 2.3.1. B. fragilis group The most commonly studied anaerobic pathogens have been the B. fragilis group species; these studies report variable numbers of isolates from the different species, usually obtained from general clinical sources. In 2004, Jones
451
et al. (2004b) reported doripenem to be active at ≤1 μg/mL against all 26 B. fragilis strains studied. Snydman et al. (2008) reported doripenem's activity against 404 B fragilis group species isolates and 123 Gram-positive anaerobic isolates. They noted that doripenem had similar activity to imipenem, meropenem, and piperacillin–tazobactam but was 2- to 4fold “more active” than ertapenem against B. fragilis group species (Snydman et al., 2008). They note that “only 3 (of 198) isolates of B. fragilis were nonsusceptible to doripenem” but used 16 μg/mL as the resistance breakpoint. They reported data on 6 species in the B. fragilis group but did not find significant differences in the carbapenem susceptibility between them. Wexler et al. (2005) also compared the activity of doripenem, ertapenem, meropenem, and imipenem against 226 B. fragilis group isolates. The doripenem geometric mean and mode MIC values for 226 B. fragilis group isolates were 0.5 μg/mL. Although they used a susceptibility breakpoint of 4 μg/mL for doripenem, they infrequently found resistance. Although it is difficult to state exact resistance rates, they noted 3 strains of B. fragilis with doripenem MICs of 8 μg/mL and 1 with an MIC of 16 μg/mL. Several strains of Bacteroides ovatus and B. thetaiotaomicron required 2 μg/mL for inhibition, and 1 unspecified strain was resistant at 16 μg/mL. Credito et al. (2008) studied 447 anaerobic strains isolated between 2003 and 2007 recovered mostly from patients with intra-abdominal and pelvic infections and reported that all B. thetaiotaomicron (n = 30), Bacteroides vulgatus (n = 20), and Bacteroides distasonis (n = 20) strains were susceptible to ≤1 μg/mL of doripenem. Although B. fragilis (n = 70) and B. ovatus (n = 10) had MIC90's of 1 μg/mL, their susceptibility ranges were 0.125 to 8 and 0.25 to 4 μg/mL, respectively, suggesting that several isolates were resistant to doripenem using the US-FDA breakpoint of ≤1 μg/mL. Moreover, they studied time–kill kinetics and found that doripenem showed bactericidal activity at 2× MIC after 12 h against 4 of 4 strains of B. fragilis and B. thetaiotaomicron strains tested. Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to have an MIC90 of 0.12 μg/mL against 22 B. fragilis gynecologic strains, although some required 2 μg/mL for inhibition. Goldstein et al. (2008) reported that 10 strains of B. fragilis and 15 strains of B. fragilis group species isolated from diabetic patients with foot infections were all susceptible to ≤1 μg/mL of doripenem, imipenem, and meropenem. Resistance to clindamycin was present in 10% and 20% of strains, respectively. Recently, Liu et al. (2008) reported on the susceptibility of blood culture isolates obtained in 2006 from Taiwanese patients and, in general, found higher rates of nonsusceptibility than reported in most other studies. For 60 B. fragilis and 30 B. thetaiotaomicron strains, they noted doripenem MIC90's of 8 and 2 μg/mL, respectively. They did not explicitly state the breakpoint chosen other than that it was “established by CLSI” and noted that 97% of B. thetaiotaomicron strains were susceptible to doripenem compared with 88% for
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B. fragilis strains. Results were similar to the other carbapenems studied, including meropenem, imipenem, and ertapenem. Comparatively, they reported resistance to B. fragilis and B. thetaiotaomicron of 23% and 33% for amoxicillin clavulanate, 35% and 37% for piperacillin, and 37% and 43% for clindamycin, respectively. They also noted that the rates of resistance encountered had increased from those tested in 2002. The marked variation in susceptibility data suggests differences in geographic distribution and by clinical source of isolate to carbapenems. However, most remain susceptible to all carbapenems, and carbapenems remain the most active of all β-lactam agents; however, resistance does occur. Up to 4% of Bacteroides spp. carry resistance genes that are not typically expressed (Hecht et al., 2007). Isolates producing zinc metallo-β-lactamases, encoded by ccrA and cfiA, remain relatively rare. However, performing periodic susceptibility surveillance is a prudent measure to monitor continued activity. 2.3.2. Prevotella and Porphyromonas spp Various authors have studied doripenem's activity against Prevotella spp. Credito et al. (2008) reported that all isolates of Prevotella bivia, Prevotella disiens, Prevotella corporis, and Prevotella buccae were susceptible to ≤0.25 μg/mL of doripenem. Goldstein et al. (2008) tested 14 P. bivia strains recovered from diabetic foot infections and found all to be susceptible to ≤0.12 μg/mL of doripenem, imipenem, and meropenem; for comparison, ertapenem required ≤0.5 μg/ mL for inhibition of all strains. Seventeen strains of Porphyromonas spp. were inhibited by 0.06 μg/mL of doripenem. Wexler et al. (2005) studied 57 diverse Prevotella spp. and noted geometric mean MICs of 0.1 to 0.2 μg/mL; several isolates of P. bivia/disiens required up to 4 μg/mL for inhibition. Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to be active against 28 P. bivia gynecologic isolates with an MIC90 of 1 μg/mL, although some isolates required 4 μg/mL for inhibition. 2.3.3. Fusobacterium spp Limited data exist about doripenem's activity against Fusobacterium spp. One report in 2008 (Credito et al., 2008) showed that all strains of Fusobacterium nucleatum, Fusobacterium necrophorum, Fusobacterium varium, and Fusobacterium mortiferum were susceptible to ≤1 μg/mL of doripenem, imipenem, meropenem, and ertapenem, except for 1 isolate of F. varium that required 2 μg/mL of imipenem for inhibition. Wexler et al. (2005) reported 15 unspecified fusobacteria inhibited by ≤1 μg/mL doripenem, although 1 strain was resistant to ertapenem at N32 μg/mL. 2.3.4. Bilophila wadsworthia and Sutterella wadsworthensis Twenty-one isolates of B. wadsworthia were all susceptible to ≤0.12 μg/mL of doripenem, meropenem, and ertapenem and ≤0.25 μg/mL of imipenem (Wexler et al., 2005). Twelve isolates of S. wadsworthensis had a geometric
mean MIC of 2.3 μg/mL with a range of 0.06 to 32 μg/mL and an MIC50 and MIC90 of 4 and 8 μg/mL, respectively, to doripenem. Surprisingly, other carbapenems were more active than doripenem, with ertapenem having a geometric mean MIC of 0.3 μg/mL to the same isolates and meropenem and imipenem having geometric mean MICs of 1.1 and 1.2 μg/mL, respectively. 2.3.5. Clostridium spp Hecht et al. (2007) reported the in vitro activity of 15 agents tested against 110 toxogenic Clostridium difficile strains collected from 1983 to 2004. Doripenem was noted to be “very active”, with an MIC50 of 1 μg/mL and an MIC90 of 2 μg/mL, a geometric mean MIC of 1.19 μg/mL, and a narrow range of inhibitory concentrations (1–4 μg/mL). They speculated that these levels “may be achievable in the colon” and thus might result in a lower C. difficile-associated disease rate. Meropenem also had a similar MIC range but was generally 1 dilution less active and had a geometric mean MIC of 1.87 μg/mL. Wexler et al. (2005) tested 6 strains of C. difficile and reported that “3 to 5 of the 6 strains required 8 μg/mL of ertapenem, imipenem, or meropenem for inhibition”, whereas 5 strains were susceptible to ≤2 μg/ mL of doripenem and 1 required 4 μg/mL for inhibition. Another report (Jones et al., 2005) tested 10 C. difficile strains and reported that all were susceptible to ≤2 μg/mL of doripenem and that ertapenem was less active. Credito et al. (2008) tested 20 strains, none of which were β-lactamase producers, and found that doripenem and meropenem have MIC50's of 2 μg/mL and MIC90's of 4 μg/mL, whereas imipenem and ertapenem had MIC90's of 8 μg/mL. In addition, the same group performed time–kill studies with 2 strains of C. difficile and found that doripenem and imipenem killed both strains at the 2× MIC after 48 h, but only at the 90% level. All Clostridium perfringens studied have been very susceptible to doripenem. Credito et al. (2008) studied 30 strains that were susceptible to ≤0.06 μg/mL, which was similar to the finding of Goldstein et al. (2008) (0.03 μg/ mL) and Snydman et al. (2008) (0.12 μg/mL). Other species of clostridia, including Clostridium ramosum, Clostridium innocuum, and Clostridium clostridioforme, that have demonstrated resistance to commonly used anaerobic drugs were all inhibited by ≤1 μg/mL of doripenem (Credito et al., 2008). 2.3.6. Anaerobic Gram-positive cocci Anaerobic Gram-positive cocci tend to be very susceptible to all carbapenems (Credito et al., 2008; Goldstein et al., 2008; Mikamo et al., 2000; Snydman et al., 2008). Goldstein et al. (2008) found that 99 strains, including 30 of Finegoldia magna and 20 of Peptoniphilus asaccharolyticus, isolated from diabetic foot infections were susceptible to ≤0.5 μg/mL of doripenem. Credito et al. (2008) reported that all F. magna (n = 10), Parvimonas micra (n = 10), and P. asaccharolyticus (n =
E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454
10) were susceptible to ≤0.125 μg/mL of doripenem but that at least 1 strain of Peptostreptococcus anaerobius required 2 μg/mL for inhibition by doripenem, meropenem, and ertapenem. They also reported that in time–kill studies, 1 strain of F. magna did not show 99.9% killing at 48 h at the MIC value of doripenem, imipenem, and ertapenem and that “1 additional strain of F. magna was not bactericidally inhibited by meropenem at 2× MIC after 48 h”. Snydman et al. (2008) also noted that 10 F. magna strains were susceptible to ≤0.125 μg/mL of doripenem and ertapenem, and Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to be active at ≤0.5 μg/mL against 21 F. magna strains isolated from patients with female gynecologic infections isolated in 1997 to 1998. 2.4. Animal models Mikamo et al. (2000) developed a rat pyometria model and injected Sprague–Dawley rats with Escherichia coli and B. fragilis, and analyzed viable counts in the uterine contents to compare treatment with imipenem or doripenem with untreated rats, using 6 rats per group. Reduction in viable counts of both organisms was significantly greater in both treatment groups as compared with untreated controls. Based on the in vitro activity against other gynecologic aerobic pathogens in their study, they concluded that doripenem may be useful for treating polymicrobial infections in the fields of obstetrics and gynecology. 2.5. Clinical trials Kaniga et al (Abstract E-264; Proceedings of the 47th Inter Conf Antimicrob Agents Chemother, September 17 to 20, 2007, Chicago, IL, p186) reported the results from 2 phase 3 multinational trials of doripenem in 962 patients with complicated intra-abdominal infections. Anaerobes (not speciated) accounted for 35% of the 962 isolates; doripenem was active at ≤0.5 μg/mL against 93% of anaerobic isolates with a range of ≤0.03 to N32 μg/mL. They noted that “doripenem was more potent than meropenem, ertapenem, … and similar to imipenem against anaerobes”. Lucasti et al. (2008) reported on one of these phase 3 trials comparing doripenem 500 mg iv tid with meropenem 1 g iv tid in 319 evaluable patients. The doripenem cure rate was 85.9% compared with 85.3% for meropenem at the test of cure. Approximately 60% of both groups consisted of patients with complicated appendicitis. There were no significant differences in microbiologic cure rates when analyzed by anaerobic species. Of the 173 anaerobes isolated, 101 were Bacteroides spp. organisms recovered from 48.9% to 49.8% of patients, with B. fragilis being the most frequent isolate (14.7–16.9% of patients). Cure rates for infections involving B. fragilis group species were 68.3% (75 strains) for doripenem-treated patients and 84.3% (89 strains) for meropenem-treated patients. For patients with Gram-positive anaerobic infections, the cure rates were 81% for both
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groups. The US-FDA approved doripenem for intraabdominal infections in 2007 (Table 2). 3. Conclusions Doripenem has activity against nearly all genera and species of Gram-negative and Gram-positive anaerobic bacteria in vitro, including B. fragilis group species, with the exception of S. wadsworthensis. This activity is comparable with the other extant carbapenems (ertapenem, imipenem, meropenem). Although resistance is possible, it remains relatively rare. In addition, doripenem has been found to be efficacious in an animal model and in reported clinical studies of mixed aerobic/anaerobic complicated intra-abdominal infections. References Brown SD, Traczewski MM (2005) Comparative in vitro antimicrobial activity of a new carbapenem, doripenem: tentative disc diffusion criteria and quality control. J Antimicrob Chemother 55:944–949. Clinical and Standards Institute (CLSI) (2007) Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard - seventh edition, M11-A7. Wayne, PA: CLSI. Credito KL, Ednie LM, Appelbaum PC (2008) Comparative antianaerobic activities of doripenem determined by MIC and time–kill analysis. Antimicrob Agents Chemother 52:365–373. Doribax Package Insert (2008) Doribax. Raritan, NJ. (Ortho-McNeil Pharmaceutical, Inc.). Available at http://www.doribax.com/doribax/ shared/pi/doribax.pdf#zoom=100. Edwards R, Read PN (2000) Expression of the carbapenemase gene (cfiA) in Bacteroides fragilis. J Antimicrob Chemother 46:1009–1012. Goldstein EJC, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT (2008) In vitro activities of doripenem and six comparator drugs against 423 aerobic and anaerobic bacterial isolates from infected diabetic foot wounds. Antimcrob Agents Chemother 52:761–766. Hecht DW (2004) Prevalence of antibiotic resistance in anaerobic bacteria: worrisome developments. Clin Infect Dis 39:92–97. Hecht DW, Gulang MA, Sambol SP, Osmolski JR, Johnson S, Gerding DN (2007) In vitro activity of 15 antimicrobial agents against 110 toxogenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother 51:2716–2719. Jones RN, Huynh HK, Biedenbach DL (2004a) Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrob Agents Chemother 48:3136–3140. Jones RN, Hunyh HK, Biedenbach DJ, Fritsche TR, Sader HS (2004b) Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluation. J Antimicrob Chemother 54:144–154. Jones RN, Sader HS, Fritsche TR (2005) Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various β-lactamase resistance mechanisms. Diagn Microbiol Infect Dis 52:71–74. Liu CY, Huang YT, Laio CH, Yen LC, Lin HY, Hseuh PR (2008) Increasing trends in antimicrobial resistance among clinically important anaerobes and Bacteroides fragilis isolates causing nosocomial infections: emerging resistance to carbapenems. Antimicrob Agents Chemother 52:3161–3168. Lucasti C, Jasovich A, Umeh O, Jiang JJ, Kanaga K, Friedland I (2008) Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double blind no inferiority study. Clin Ther 5: 868–883.
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Mikamo H, Izumi K, Hua YX, Hayasaki Y, Sato Y, Tamaya T (2000) In vitro and in vivo antibacterial activities of a new injectable carbapenem, S-4661, against gynaecological pathogens. J Antimicrob Chemother 46: 471–474. Podglajen I, Breiul J, Bordon F, Gutmann L, Collatz E (1992) A silent carbapenemase gene in strains of Bacteroides fragilis can be expressed after a one-step mutation. FEMS Microbiol Lett 70:21–29.
Snydman DR, Jacobus NV, McDermott LA (2008) In vitro activities of doripenem, a new broad-spectrum, carbapenem, against recently collected clinical anaerobic isolates, with emphasis on the Bacteroides fragilis group. Antimicrob Agents Chemother 52:4492–4496. Wexler HM, Engel AE, Glass D, Li C (2005) In vitro activities of doripenem and comparator agents against 364 anaerobic clinical isolates. Antimicrob Agents Chemother 49:4413–4417.
Diagnostic Microbiology and Infectious Disease 63 (2009) 447 – 454 www.elsevier.com/locate/diagmicrobio
Activity of a novel carbapenem, doripenem, against anaerobic pathogens Ellie J.C. Goldstein⁎, Diane M. Citron RM Alden Research Laboratory, Culver City, CA 90230, USA The David Geffen School of Medicine at Los Angeles, CA 90074, USA Received 23 January 2009; accepted 23 January 2009
Abstract Doripenem, a synthetic 1-β-methyl carbapenem, has a broad-spectrum of activity against almost all species of anaerobic bacteria, including all Bacteroides fragilis group species, most with MIC90 results at ≤1 μg/mL (with the exception of Sutterella wadsworthensis). Against Clostridium difficile strains, it has a narrow range of inhibitory concentrations (1–4 μg/mL) that “may be achievable in the colon”, potentially resulting in lower disease rates. It has been shown to be active in vitro against strains isolated from a variety of clinical infections, including bacteremias, diabetic foot and other soft tissues infections and in intra-abdominal and pelvic sites. In addition, a study of a pyometrium animal model of mixed infections noted a better microbiologic response than with imipenem. Two phase 3 multinational clinical trials of complicated mixed aerobic/anaerobic intra-abdominal infections noted “noninferiority” of doripenem when compared with meropenem, but in vitro against the anaerobes, it was “more potent than meropenem, ertapenem, … and similar to imipenem”. Doripenem activity against anaerobes seems comparable with the other extant carbapenems. Although resistance among anaerobic bacteria to this agent is possible, it remains relatively rare. © 2009 Elsevier Inc. All rights reserved. Keywords: Doripenem; Anaerobes; Carbapenems; Resistance
1. Introduction Doripenem is a synthetic 1-β-methyl carbapenem with a broad-spectrum of activity (Jones et al., 2004b). Its structure confers stability against dehydropeptidase-1 and many β-lactamases (Jones et al., 2004a, 2005). Most attention has been focused on doripenem aerobic Gram-positive activity that is similar to imipenem and its aerobic Gramnegative rod activity that is similar to meropenem. A few studies have reported on its in vitro anaerobic activity (Jones et al., 2004b). The gene for carbapenemase is present in some strains of Bacteroides, but it may be expressed only partially or not at all, resulting in a large range of MIC values (Edwards and Read, 2000; Hecht, 2004; Podglajen et al., 1992). In addition,) Wexler et al. (2005) have noted that efflux “is not a clinically significant resistance mechanism” for anaerobes against doripenem. Doripenem has been
⁎ Corresponding author. Santa Monica, CA 904040, USA. Tel.: +1-310315-1511; fax: +1-310-315-3663. E-mail address: [email protected] (E.J.C. Goldstein). 0732-8893/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2009.01.022
approved by the United States Food and Drug Administration (US-FDA) for clinical use in complicated intraabdominal infections. This manuscript reviews the extant data on doripenem's activity against anaerobic bacteria. In vitro data limited to those isolates where investigators reported on ten or more isolates are noted in Table 1. Table 2 lists the microbiologic cure rates for anaerobic organisms for which doripenem is approved by the US-FDA. 2. Results and review 2.1. Breakpoints Brown and Traczewski (2005) studied 10 ATCC reference strains, including 3 anaerobic organisms, and, based on modal MIC values observed ±1 log2 dilution, proposed tentative MIC breakpoints for doripenem of ≤1 μg/mL for streptococci and ≤2 μg/mL for all other genera. For anaerobes, they used a broth microdilution method with Brucella broth supplemented with 5% lysed horse blood, 1 mg/L of vitamin K1, and 5 mg/L of hemin. They did not recommend any quality control (QC) ranges for Eubacterium
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Table 1 In vitro activity of doripenem and other carbapenems against anaerobic bacteria Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
B. fragilis
26
Doripenem Meropenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
0.125 to 1 0.06 to 2 0.125 to 2 0.25 to N32 0.12 to N32 0.12 to N32 0.12 to N32 0.06 to 2 0.06 to 2 0.06 to 2 0.25 to 0.25 0.12 to 0.25 0.03 to 0.12 0.25 to 1 0.25 to 16 0.12 to 8 0.06 to 2 0.12 to 4 0.12 to 16 0.12 to 16 0.12/16 0.25 to 16 0.12 to 8 0.06 to 8 0.03 to 2 0.12 to 8 0.5 to 8 0.12 to 8 0.25 to 8 0.25 to 16 0.12 to 2 0.06 to 1 0.03 to 1 0.06 to 2 0.12 to 8 0.12 to 8 0.12 to 8 0.12 to 8 0.25 to 0.5 0.12 to 0.5 0.25 to 0.5 0.5 to 2 0.12 to 2 0.03 to 0.5 0.06 to 0.5 0.12 to 2 0.25 to 4 0.12 to 4 0.12 to 4 0.25 to 16 0.25 to 4 0.25 to 4 0.12 to 2 0.5 to 8 0.25 to 4 0.12 to 4 0.12 to 4 0.25 to 8 0.15 to 2 0.25 to 8 0.12 to 8 0.25 to 8
0.25/0.5 0.12/1 0.5/1 0.5/2 0.25/8 0.5/4 0.25/4 0.12/0.5 0.12/0.5 0.12/0.5 0.25/0.25 0.12/0.25 0.12/0.12 0.12/0.12 0.5/1 0.12/0.5 0.25/0.5 0.25/0.5 0.5/1 0.25/1 0.5/1 0.5/2 0.25/1 0.12/1 0.12/0.25 0.25/2 0.5/2 0.25/2 0.5/4 1/4 0.5/1 0.25/0.5 0.5/1 0.5/2 0.5/1 0.5/2 1/2 2/4 0.25/0.5 0.25/0.5 0.25/0.5 0.5/1 0.5/1 0.25/0.5 0.25/0.5 0.5/1 0.5/2 0.5/2 0.5/2 1.0/4 0.25/1 0.25/0.5 0.25/0.5 0.5/2 0.5/2 0.25/2 0.5/2 0.5/2 0.5/2 1/2 0.25/2 1/4
Jones
60
22
10
81
198
70
B. thetaiotaomicron
30
42
78
30
B. ovatus
20
78
10
Bacteroides caccae
16
Parabacteroides distasonis
15
Sourcesb
Liu
Blood
Mikamo
GYN
Goldstein
DFI
Wexler
Various
Snydman
Various
Credito
Various
Liu
Blood
Wexler
Various
Snydman
Various
Credito
Various
Wexler
Various
Snydman
Various
Credito
Various
Snydman
Various
Snydman
Various
E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454
449
Table 1 (continued) Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
Sourcesb
20
Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
0.25 to 1 0.12 to 1 0.25 to 1 0.5 to 2 0.12 to 1 0.12 to 2 0.25 to 1 0.12 to 2 0.12 to 2 0.25 to 4 0.25 to 2 0.12 to 4 0.12 to 1 0.12 to 1 0.06 to 1 0.06 to 2 0.12 to 4 0.12 to 4 0.12 to 8 b0.015 to 0.12 b0.015 to 0.12 b0.015 to 0.03 0.03 to 0.5 0.06 to 0.25 0.03 to 0.25 b0.016 to 0.12 0.06 to 0.5 0.03 to 0.125 0.03 to 0.12 0.03 to 0.12 0.03 to 0.23 0.03 to 0.06 b0.015 to 0.06 b0.016 to 0.06 b0.016 to 0.12 0.06 to 0.12 b0.016 to 0.06 0.03 to 0.06 0.06 to 0.12 b0.016 to 0.03 b0.016 to 0.06 b0.016 to 0.06 b0.016 to 0.06 b0.016 to 0.25 ≤0.016 to 0.12 ≤0.016 to 0.25 ≤0.016 to 0.12 0.12 to 1 0.06 to 1 0.25 to 1 0.06/0.5 0.06 to 1 0.06 to 0.25 0.5 to 2 0.06 to 0.12 0.03 to 0.12 0.03 to .012 0.06 to 0.25 0.03 to 0.12 0.06 to 31 0.03 to N32 0.03 to 16 0.03 to 1
0.5/1 0.12/0.5 0.5/1 0.5/1 0.5/1 0.25/0.5 1/1 0.5/2 0.5/2 0.5/2 1/2 0.5/2 0.25/1 0.25/1 0.5/1 0.12/2 0.25/1 0.25/1 0.25/8 0.06/0.12 0.06/0.12 0.03/0.02 0.25/0.5 0.06/0.12 0.06/0.12 0.03/0.06 0.25/0.25 0.06/0.12 0.03/0.12 0.03/0.12 0.06/0.25 0.03/0.06 0.03/0.06 0.03/0.06 0.03/0.06 0.06/0.12 0.06/0.06 0.03/0.03 0.12/0.12 b0.016/0.03 ≤0.016/0.03 0.03/0.03 ≤0.016/0.03 b0.016/0.25 ≤0.016/0.12 ≤0.016/0.25 ≤0.016/0.12 0.25/1 1/1 1/1 0.06/0.5 0.12/0.25 0.12/0.25 1/1 0.06/0.25 0.12/0.12 0.06/0.12 012/0.25 0.12/0.12 4/8 4/4 1/4 0.5/1
Credito
Various
Snydman
Various
Snydman
Various
Credito
Various
Mikamo
GYN
Goldstein
DFI
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Credito
Various
Wexler
Various
Wexler
Various
Bacteroides uniformis
21
B. vulgatus
31
20
P. bivia
28
14
30
P. disiens
10
P. corporis
10
P. buccae
10
F. nucleatum
20
F. necrophorum
18
F. mortiferum
10
F. varium
10
B. wadsworthia
21
S. wadsworthensis
12
(continued on next page)
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E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454
Table 1 (continued) Organism
No. of isolates
Drug
Range (µg/mL)a
MIC50/90 (µg/mL)a
Reference
Sourcesb
C. difficile
16
Doripenem Meropenem Ertapenem Doripenem Meropenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem Doripenem Meropenem Imipenem Ertapenem
b0.015 to 0.25 1 to 4 4 to 8 0.5 to 4 1 to 4 1 to 4 1 to 4 4 to 8 4 to 8 b0.015 to 0.03 ≤0.015 0.03 to 0.12 0.03 to 0.12 0.06 to 0.12 0.06 to 0.12 0.25 to 4 0.06 to 0.25 ≤0.016 to 0.06 ≤0.016 to 0.03 ≤0.016 to 0.12 ≤0.016 to 0.12 0.015 to 0.5 0.015 to 0.25 0.03 to 1 ≤0.015 to 0.25 ≤0.015 to 0.5 ≤0.015 to 0.25 ≤0.015 to 1 0.06 to 0.12 0.06 to 0.25 0.12 to 0.25 0.06 to 0.12 0.06 to 0.12 0.06 to 0.12 0.03 to 0.06 0.03 to 0.06 b0.015 to 0.12 ≤0.015 to 0.12 ≤0.015 to 0.06 ≤0.015 to 1 ≤0.016 to 0.12 ≤0.016 to 0.12 ≤0.016 to 0.06 ≤0.016 to 0.5 0.12 to 2 0.25 to 2 0.06 to 2 0.25 to 2 b0.016 to 0.12 0.03 to 0.25 0.03 to 0.12 ≤0.016 to 0.25 0.03 to 0.25 0.06 to 0.5 ≤0.015 ≤0.06 to 0.5 0.06 to 0.06 0.06 to 0.06 0.06 to 0.12 0.06 to 0.06
0.03/0.06 2/2 4/4 1/2 2/2 2/4 1/4 8/8 4/8 b0.015/0.03 ≤0.015/≤0.015 0.06/0.12 0.06/0.12 0.06/0.12 0.06/0.12 0.5/0.5 0.06/0.25 0.03/0.03 ≤0.016/≤0.016 0.06/0/12 0.06/0.12 0.06/0.12 0.03/0.12 0.12/1 0.06/0.12 0.06/0.12 0.03/0.06 0.06/0.12 0.12/0.12 0.12/0.12 0.25/0.25 0.12/0.12 0.06/0.12 0.06/0.12 0.06/0.06 0.06/0.06 b0.015/0.06 ≤0.015/0.12 0.015/0.03 ≤0.015/0.25 ≤0.016/0.03 ≤0.016/0.03 ≤0.016/0.03 ≤0.016/0.06 0.25/2 0.25/2 0.06/1 0.5/2 b0.016/0.06 0.03/0.25 0.03/0.06 0.03/0.12 0.06/0.12 0.12/0.25 ≤0.015/≤0.015 0.12/0.25 0.06/0.06 0.06/0.06 0.06/0.06 0.06/0.06
Jones
Various
Hecht
Various
Credito
Various
Goldstein
DFI
Snydman
Various
Credito
Various
Mikamo
GYN
Goldstein
DFI
Snydman
Various
Credito
Various
Goldstein
DFI
Credito
Various
Credito
Various
Credito
Various
Goldstein
DFI
Snydman
Various
110 20
C. perfringens
10
13
30
F. magna
21
30
10
10
P. asaccharolyticus
20
10
P. anaerobius
10
P. micra
10
Propionibacterium acnes
14
18
a b
Breakpoints for anaerobes: doripenem, ≤1 μg/mL, and meropenem, imipenem, ertapenem, ≤4 μg/mL. DFI = diabetic foot infections; GYN = gynecologic infections.
E.J.C. Goldstein, D.M. Citron / Diagnostic Microbiology and Infectious Disease 63 (2009) 447–454 Table 2 Microbiologic cure rates for specific pathogens isolated in complicated intraabdominal infections (Doribax® package insert) Organism
No. of strains
No./% cured
B. fragilis B. thetaiotaomicron B. caccae B. uniformis B. vulgatus Non-fragilis Bacteroides Total B. fragilis group
67 34 25 22 11 14 173
56/83.6% 30/88.2% 23/92% 19/86.4% 11/100% 13/92.9% 152 /87.9%
Breakpoint for anaerobes: doripenem, ≤1 μg/mL; imipenem, ≤4 μg/mL; meropenem, ≤4 μg/mL; ertapenem, ≤4 μg/mL.
lentum ATCC 43055 but suggested a QC range of 0.12 to 0.5 μg/mL for Bacteroides fragilis ATCC 25285 (95.5% within range) and 0.12 to 1 μg/mL for Bacteroides thetaiotaomicron ATCC 29741 (97.2% within range). Although Brown and Traczewski's (1) recommendations of QC ranges for B. fragilis ATCC 25285 and B. thetaiotaomicron ATCC 29741 were accepted by the Antimicrobial Susceptibility Testing Subcommittee of the Clinical and Laboratory Standards Institute (CLSI, formerly National Committee on Clinical Laboratory Standards) in the June 2004 meeting and have since been published in the M11-A7 (CLSI, 2007) document, the US-FDA accepted their proposed QC ranges but established a breakpoint of ≤1 μg/ mL for anaerobes (Doribax Package Insert, 2008). This selection of 1 μg/mL as an anaerobic organism breakpoint needs to be considered when interpreting the published literature and the authors' statements of percentage susceptibility, which have been published in that interim. The anaerobic breakpoints for meropenem, imipenem, and ertapenem remain ≤4 μg/mL. This disparity may also be reconciled soon. 2.2. Pharmacokinetics After a 1-h infusion of 500 mg of doripenem, the mean Cmax in 24 healthy volunteers was 23 μg/mL (Standard deviation, 6.6 μg/mL) and the area under the curve (AUC) was 36.3 (SD, 8.8) μg h/mL (Doribax® package insert). It penetrates into the peritoneal and retroperitoneal fluid at concentrations that exceed the anaerobic breakpoint. After a 30-min 500-mg infusion, it achieved concentrations of 9.53 to 13.9 μg/mL at 90 min and a tissue to plasma concentration ratio of 516% (311–842%) at 6.5 h (14). After a 250-mg 30-min infusion, doripenem achieved peritoneal exudate concentrations of 2.36 to 5.17 μg/mL and a tissue to plasma concentration ratio of 160% (32.2– 322%) at 4.5 h (Doribax® package insert). 2.3. In vitro susceptibility studies 2.3.1. B. fragilis group The most commonly studied anaerobic pathogens have been the B. fragilis group species; these studies report variable numbers of isolates from the different species, usually obtained from general clinical sources. In 2004, Jones
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et al. (2004b) reported doripenem to be active at ≤1 μg/mL against all 26 B. fragilis strains studied. Snydman et al. (2008) reported doripenem's activity against 404 B fragilis group species isolates and 123 Gram-positive anaerobic isolates. They noted that doripenem had similar activity to imipenem, meropenem, and piperacillin–tazobactam but was 2- to 4fold “more active” than ertapenem against B. fragilis group species (Snydman et al., 2008). They note that “only 3 (of 198) isolates of B. fragilis were nonsusceptible to doripenem” but used 16 μg/mL as the resistance breakpoint. They reported data on 6 species in the B. fragilis group but did not find significant differences in the carbapenem susceptibility between them. Wexler et al. (2005) also compared the activity of doripenem, ertapenem, meropenem, and imipenem against 226 B. fragilis group isolates. The doripenem geometric mean and mode MIC values for 226 B. fragilis group isolates were 0.5 μg/mL. Although they used a susceptibility breakpoint of 4 μg/mL for doripenem, they infrequently found resistance. Although it is difficult to state exact resistance rates, they noted 3 strains of B. fragilis with doripenem MICs of 8 μg/mL and 1 with an MIC of 16 μg/mL. Several strains of Bacteroides ovatus and B. thetaiotaomicron required 2 μg/mL for inhibition, and 1 unspecified strain was resistant at 16 μg/mL. Credito et al. (2008) studied 447 anaerobic strains isolated between 2003 and 2007 recovered mostly from patients with intra-abdominal and pelvic infections and reported that all B. thetaiotaomicron (n = 30), Bacteroides vulgatus (n = 20), and Bacteroides distasonis (n = 20) strains were susceptible to ≤1 μg/mL of doripenem. Although B. fragilis (n = 70) and B. ovatus (n = 10) had MIC90's of 1 μg/mL, their susceptibility ranges were 0.125 to 8 and 0.25 to 4 μg/mL, respectively, suggesting that several isolates were resistant to doripenem using the US-FDA breakpoint of ≤1 μg/mL. Moreover, they studied time–kill kinetics and found that doripenem showed bactericidal activity at 2× MIC after 12 h against 4 of 4 strains of B. fragilis and B. thetaiotaomicron strains tested. Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to have an MIC90 of 0.12 μg/mL against 22 B. fragilis gynecologic strains, although some required 2 μg/mL for inhibition. Goldstein et al. (2008) reported that 10 strains of B. fragilis and 15 strains of B. fragilis group species isolated from diabetic patients with foot infections were all susceptible to ≤1 μg/mL of doripenem, imipenem, and meropenem. Resistance to clindamycin was present in 10% and 20% of strains, respectively. Recently, Liu et al. (2008) reported on the susceptibility of blood culture isolates obtained in 2006 from Taiwanese patients and, in general, found higher rates of nonsusceptibility than reported in most other studies. For 60 B. fragilis and 30 B. thetaiotaomicron strains, they noted doripenem MIC90's of 8 and 2 μg/mL, respectively. They did not explicitly state the breakpoint chosen other than that it was “established by CLSI” and noted that 97% of B. thetaiotaomicron strains were susceptible to doripenem compared with 88% for
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B. fragilis strains. Results were similar to the other carbapenems studied, including meropenem, imipenem, and ertapenem. Comparatively, they reported resistance to B. fragilis and B. thetaiotaomicron of 23% and 33% for amoxicillin clavulanate, 35% and 37% for piperacillin, and 37% and 43% for clindamycin, respectively. They also noted that the rates of resistance encountered had increased from those tested in 2002. The marked variation in susceptibility data suggests differences in geographic distribution and by clinical source of isolate to carbapenems. However, most remain susceptible to all carbapenems, and carbapenems remain the most active of all β-lactam agents; however, resistance does occur. Up to 4% of Bacteroides spp. carry resistance genes that are not typically expressed (Hecht et al., 2007). Isolates producing zinc metallo-β-lactamases, encoded by ccrA and cfiA, remain relatively rare. However, performing periodic susceptibility surveillance is a prudent measure to monitor continued activity. 2.3.2. Prevotella and Porphyromonas spp Various authors have studied doripenem's activity against Prevotella spp. Credito et al. (2008) reported that all isolates of Prevotella bivia, Prevotella disiens, Prevotella corporis, and Prevotella buccae were susceptible to ≤0.25 μg/mL of doripenem. Goldstein et al. (2008) tested 14 P. bivia strains recovered from diabetic foot infections and found all to be susceptible to ≤0.12 μg/mL of doripenem, imipenem, and meropenem; for comparison, ertapenem required ≤0.5 μg/ mL for inhibition of all strains. Seventeen strains of Porphyromonas spp. were inhibited by 0.06 μg/mL of doripenem. Wexler et al. (2005) studied 57 diverse Prevotella spp. and noted geometric mean MICs of 0.1 to 0.2 μg/mL; several isolates of P. bivia/disiens required up to 4 μg/mL for inhibition. Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to be active against 28 P. bivia gynecologic isolates with an MIC90 of 1 μg/mL, although some isolates required 4 μg/mL for inhibition. 2.3.3. Fusobacterium spp Limited data exist about doripenem's activity against Fusobacterium spp. One report in 2008 (Credito et al., 2008) showed that all strains of Fusobacterium nucleatum, Fusobacterium necrophorum, Fusobacterium varium, and Fusobacterium mortiferum were susceptible to ≤1 μg/mL of doripenem, imipenem, meropenem, and ertapenem, except for 1 isolate of F. varium that required 2 μg/mL of imipenem for inhibition. Wexler et al. (2005) reported 15 unspecified fusobacteria inhibited by ≤1 μg/mL doripenem, although 1 strain was resistant to ertapenem at N32 μg/mL. 2.3.4. Bilophila wadsworthia and Sutterella wadsworthensis Twenty-one isolates of B. wadsworthia were all susceptible to ≤0.12 μg/mL of doripenem, meropenem, and ertapenem and ≤0.25 μg/mL of imipenem (Wexler et al., 2005). Twelve isolates of S. wadsworthensis had a geometric
mean MIC of 2.3 μg/mL with a range of 0.06 to 32 μg/mL and an MIC50 and MIC90 of 4 and 8 μg/mL, respectively, to doripenem. Surprisingly, other carbapenems were more active than doripenem, with ertapenem having a geometric mean MIC of 0.3 μg/mL to the same isolates and meropenem and imipenem having geometric mean MICs of 1.1 and 1.2 μg/mL, respectively. 2.3.5. Clostridium spp Hecht et al. (2007) reported the in vitro activity of 15 agents tested against 110 toxogenic Clostridium difficile strains collected from 1983 to 2004. Doripenem was noted to be “very active”, with an MIC50 of 1 μg/mL and an MIC90 of 2 μg/mL, a geometric mean MIC of 1.19 μg/mL, and a narrow range of inhibitory concentrations (1–4 μg/mL). They speculated that these levels “may be achievable in the colon” and thus might result in a lower C. difficile-associated disease rate. Meropenem also had a similar MIC range but was generally 1 dilution less active and had a geometric mean MIC of 1.87 μg/mL. Wexler et al. (2005) tested 6 strains of C. difficile and reported that “3 to 5 of the 6 strains required 8 μg/mL of ertapenem, imipenem, or meropenem for inhibition”, whereas 5 strains were susceptible to ≤2 μg/ mL of doripenem and 1 required 4 μg/mL for inhibition. Another report (Jones et al., 2005) tested 10 C. difficile strains and reported that all were susceptible to ≤2 μg/mL of doripenem and that ertapenem was less active. Credito et al. (2008) tested 20 strains, none of which were β-lactamase producers, and found that doripenem and meropenem have MIC50's of 2 μg/mL and MIC90's of 4 μg/mL, whereas imipenem and ertapenem had MIC90's of 8 μg/mL. In addition, the same group performed time–kill studies with 2 strains of C. difficile and found that doripenem and imipenem killed both strains at the 2× MIC after 48 h, but only at the 90% level. All Clostridium perfringens studied have been very susceptible to doripenem. Credito et al. (2008) studied 30 strains that were susceptible to ≤0.06 μg/mL, which was similar to the finding of Goldstein et al. (2008) (0.03 μg/ mL) and Snydman et al. (2008) (0.12 μg/mL). Other species of clostridia, including Clostridium ramosum, Clostridium innocuum, and Clostridium clostridioforme, that have demonstrated resistance to commonly used anaerobic drugs were all inhibited by ≤1 μg/mL of doripenem (Credito et al., 2008). 2.3.6. Anaerobic Gram-positive cocci Anaerobic Gram-positive cocci tend to be very susceptible to all carbapenems (Credito et al., 2008; Goldstein et al., 2008; Mikamo et al., 2000; Snydman et al., 2008). Goldstein et al. (2008) found that 99 strains, including 30 of Finegoldia magna and 20 of Peptoniphilus asaccharolyticus, isolated from diabetic foot infections were susceptible to ≤0.5 μg/mL of doripenem. Credito et al. (2008) reported that all F. magna (n = 10), Parvimonas micra (n = 10), and P. asaccharolyticus (n =
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10) were susceptible to ≤0.125 μg/mL of doripenem but that at least 1 strain of Peptostreptococcus anaerobius required 2 μg/mL for inhibition by doripenem, meropenem, and ertapenem. They also reported that in time–kill studies, 1 strain of F. magna did not show 99.9% killing at 48 h at the MIC value of doripenem, imipenem, and ertapenem and that “1 additional strain of F. magna was not bactericidally inhibited by meropenem at 2× MIC after 48 h”. Snydman et al. (2008) also noted that 10 F. magna strains were susceptible to ≤0.125 μg/mL of doripenem and ertapenem, and Mikamo et al. (2000), using Gifu anaerobic medium, reported doripenem to be active at ≤0.5 μg/mL against 21 F. magna strains isolated from patients with female gynecologic infections isolated in 1997 to 1998. 2.4. Animal models Mikamo et al. (2000) developed a rat pyometria model and injected Sprague–Dawley rats with Escherichia coli and B. fragilis, and analyzed viable counts in the uterine contents to compare treatment with imipenem or doripenem with untreated rats, using 6 rats per group. Reduction in viable counts of both organisms was significantly greater in both treatment groups as compared with untreated controls. Based on the in vitro activity against other gynecologic aerobic pathogens in their study, they concluded that doripenem may be useful for treating polymicrobial infections in the fields of obstetrics and gynecology. 2.5. Clinical trials Kaniga et al (Abstract E-264; Proceedings of the 47th Inter Conf Antimicrob Agents Chemother, September 17 to 20, 2007, Chicago, IL, p186) reported the results from 2 phase 3 multinational trials of doripenem in 962 patients with complicated intra-abdominal infections. Anaerobes (not speciated) accounted for 35% of the 962 isolates; doripenem was active at ≤0.5 μg/mL against 93% of anaerobic isolates with a range of ≤0.03 to N32 μg/mL. They noted that “doripenem was more potent than meropenem, ertapenem, … and similar to imipenem against anaerobes”. Lucasti et al. (2008) reported on one of these phase 3 trials comparing doripenem 500 mg iv tid with meropenem 1 g iv tid in 319 evaluable patients. The doripenem cure rate was 85.9% compared with 85.3% for meropenem at the test of cure. Approximately 60% of both groups consisted of patients with complicated appendicitis. There were no significant differences in microbiologic cure rates when analyzed by anaerobic species. Of the 173 anaerobes isolated, 101 were Bacteroides spp. organisms recovered from 48.9% to 49.8% of patients, with B. fragilis being the most frequent isolate (14.7–16.9% of patients). Cure rates for infections involving B. fragilis group species were 68.3% (75 strains) for doripenem-treated patients and 84.3% (89 strains) for meropenem-treated patients. For patients with Gram-positive anaerobic infections, the cure rates were 81% for both
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groups. The US-FDA approved doripenem for intraabdominal infections in 2007 (Table 2). 3. Conclusions Doripenem has activity against nearly all genera and species of Gram-negative and Gram-positive anaerobic bacteria in vitro, including B. fragilis group species, with the exception of S. wadsworthensis. This activity is comparable with the other extant carbapenems (ertapenem, imipenem, meropenem). Although resistance is possible, it remains relatively rare. In addition, doripenem has been found to be efficacious in an animal model and in reported clinical studies of mixed aerobic/anaerobic complicated intra-abdominal infections. References Brown SD, Traczewski MM (2005) Comparative in vitro antimicrobial activity of a new carbapenem, doripenem: tentative disc diffusion criteria and quality control. J Antimicrob Chemother 55:944–949. Clinical and Standards Institute (CLSI) (2007) Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard - seventh edition, M11-A7. Wayne, PA: CLSI. Credito KL, Ednie LM, Appelbaum PC (2008) Comparative antianaerobic activities of doripenem determined by MIC and time–kill analysis. Antimicrob Agents Chemother 52:365–373. Doribax Package Insert (2008) Doribax. Raritan, NJ. (Ortho-McNeil Pharmaceutical, Inc.). Available at http://www.doribax.com/doribax/ shared/pi/doribax.pdf#zoom=100. Edwards R, Read PN (2000) Expression of the carbapenemase gene (cfiA) in Bacteroides fragilis. J Antimicrob Chemother 46:1009–1012. Goldstein EJC, Citron DM, Merriam CV, Warren YA, Tyrrell KL, Fernandez HT (2008) In vitro activities of doripenem and six comparator drugs against 423 aerobic and anaerobic bacterial isolates from infected diabetic foot wounds. Antimcrob Agents Chemother 52:761–766. Hecht DW (2004) Prevalence of antibiotic resistance in anaerobic bacteria: worrisome developments. Clin Infect Dis 39:92–97. Hecht DW, Gulang MA, Sambol SP, Osmolski JR, Johnson S, Gerding DN (2007) In vitro activity of 15 antimicrobial agents against 110 toxogenic Clostridium difficile clinical isolates collected from 1983 to 2004. Antimicrob Agents Chemother 51:2716–2719. Jones RN, Huynh HK, Biedenbach DL (2004a) Activities of doripenem (S-4661) against drug-resistant clinical pathogens. Antimicrob Agents Chemother 48:3136–3140. Jones RN, Hunyh HK, Biedenbach DJ, Fritsche TR, Sader HS (2004b) Doripenem (S-4661), a novel carbapenem: comparative activity against contemporary pathogens including bactericidal action and preliminary in vitro methods evaluation. J Antimicrob Chemother 54:144–154. Jones RN, Sader HS, Fritsche TR (2005) Comparative activity of doripenem and three other carbapenems tested against Gram-negative bacilli with various β-lactamase resistance mechanisms. Diagn Microbiol Infect Dis 52:71–74. Liu CY, Huang YT, Laio CH, Yen LC, Lin HY, Hseuh PR (2008) Increasing trends in antimicrobial resistance among clinically important anaerobes and Bacteroides fragilis isolates causing nosocomial infections: emerging resistance to carbapenems. Antimicrob Agents Chemother 52:3161–3168. Lucasti C, Jasovich A, Umeh O, Jiang JJ, Kanaga K, Friedland I (2008) Efficacy and tolerability of IV doripenem versus meropenem in adults with complicated intra-abdominal infection: a phase III, prospective, multicenter, randomized, double blind no inferiority study. Clin Ther 5: 868–883.
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