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Carbapenems are increasingly needed to treat infections caused by drug-resistant gram-negative bacilli (GNB), but carbapenem resistance is increasing. We evaluated the activity of doripenem by broth microdilution against 96 extensively drug-resistant (XDR) Acinetobacter baumannii and Klebsiella pneumoniae isolates from patients with hospital-associated infections. All isolates were non-susceptible to doripenem, but ≥1 doripenem combination demonstrated synergy (fractional inhibitory concentration index: ≤0.5 for 2 agents, ≤0.75 for 3 agents) against 7 (15%) A. baumannii and 23 (48%) K. pneumoniae isolates; doripenem with rifampin and/or polymyxin B were most active. As doripenem has unique potential for use in prolonged infusions, suggested pharmacodynamic (PD) breakpoints range from 2–8 μg/mL; synergistic activity was found for higher proportions of XDR-GNB at higher PD breakpoints with doripenem with amikacin or with rifampin. The clinical utility of these observations requires further study, as treatment options for XDR-GNB infections are limited.

Antimicrobial susceptibilities of contemporary Pseudomonas aeruginosa clinical isolates were determined from the CAPITAL 2010 surveillance program. Isolates were collected from 100 sites throughout the USA and Puerto Rico, and included isolates representing a range of patient demographics and infection types. A total of 2722 isolates were tested for susceptibility to a broad spectrum of agents, with susceptibilities ranging from 98.8% for colistin to 74% for levofloxacin. Doripenem was the most active carbapenem agent, with 88.6% of isolates susceptible, in comparison with 78.1% and 84.6% for imipenem and meropenem, respectively. Lower respiratory tract isolates and isolates from the intensive care unit setting were the least susceptible overall. Resistance rates were typically highest in lower respiratory tract isolates, with the exception of urinary tract isolates, which displayed the highest resistance for levofloxacin. Overall, multidrug-resistant isolates comprised 14.8% of the total sample population.

Doripenem is not available on many automated susceptibility testing panels. We evaluated the surrogate predictive value (SPV) of meropenem and imipenem in predicting doripenem susceptibility using the different breakpoint definitions available globally. MIC data for 736 Pseudomonas aeruginosa were extracted, and categorical interpretations were performed using Clinical and Laboratory Standards Institute (CLSI) proposed 2012, European Committee on Antimicrobial Susceptibility Testing (EUCAST), and Food and Drug Administration (FDA) breakpoints. Regardless of the breakpoint applied, very major and major errors were observed in only 0.1–0.8% and 0.1–4.5% of isolates, respectively. Meropenem's SPV was 98.6% for CLSI 2012 breakpoints, 94.0% for EUCAST, and 95.0% for FDA. Imipenem's SPV was 98.6%, 90.9%, and 97.2%, respectively. These data indicate that meropenem and imipenem would be reliable surrogate markers of doripenem susceptibility when using CLSI 2012 and FDA breakpoints. Meropenem would be recommended over imipenem for EUCAST breakpoints. However, meropenem and imipenem nonsusceptible isolates should be directly tested against doripenem since the latter antibiotic may still retain susceptibility against these isolates.

The CANWARD study (Canadian Ward Surveillance Study) assessed the antimicrobial susceptibility of a variety of available agents against 15 644 pathogens isolated from patients in Canadian hospitals between 2007 and 2009. The most active (based on MIC data) agents against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci were daptomycin, linezolid, tigecycline, and vancomycin (MRSA only) with MIC(90)'s (μg/mL) of 0.25 and 2, 2 and 2, 0.5 and 0.12, and 1, respectively. The most active agents against extended-spectrum β-lactamase-producing Escherichia coli were colistin (polymyxin E), doripenem, ertapenem, meropenem, and tigecycline with MIC(90)'s (μg/mL) of 1, ≤ 0.12, 0.25, ≤ 0.12, and 1, respectively. The most active agents against Pseudomonas aeruginosa were amikacin, cefepime, ceftazidime, colistin, doripenem, meropenem, and piperacillin-tazobactam with MIC(90)'s (μg/mL) of 32, 16, 32, 2, 4, 8, and 64, respectively. Overall, the most active agents versus Gram-positive cocci from Canadian hospitals were vancomycin, linezolid, daptomycin, and tigecycline and versus Gram-negative bacilli were amikacin, cefepime, doripenem, ertapenem (excluding Pseudomonas aeruginosa), meropenem, piperacillin-tazobactam, and tigecycline (excluding Pseudomonas aeruginosa).

Dose regimen selection in late-phase clinical trials is critical for successful drug development, the well-being of individual patients, and given the ongoing emergence of antimicrobial resistance, society as a whole. Herein we describe some of the animal pharmacokinetics-pharmacodynamics, human pharmacokinetic, and in silico modeling work that was conducted in an effort to maximize the probability of a positive clinical response to therapy and minimize the likelihood for exposure-related toxicity for doripenem in phase 3 clinical studies. Some of the dosing regimens identified have been validated as effective in phase 3 clinical studies (500 mg infused over 1 h every 8 h for complicated intra-abdominal infections), whereas others (1000 mg infused over 4 h every 8 h for hospital-acquired pneumonia) are undergoing clinical evaluation.

The in vitro activity of doripenem against prevalent nonfermentative Gram-negative bacilli and Aeromonas spp. was evaluated. The collection comprised 14979 nonduplicate clinical isolates submitted during a global Doripenem Surveillance Program conducted from 2003 through 2007. Susceptibility tests were performed using the Clinical and Laboratory Standards Institute reference broth microdilution method and the susceptibility criteria of the US Food and Drug Administration. Doripenem (MIC(90), 8 and 4 microg/mL) was 2-fold more potent than imipenem (MIC(90), >8 and 8 microg/mL) and meropenem (MIC(90), >8 and 8 microg/mL) against Pseudomonas aeruginosa and other Pseudomonas spp., covering 77.2% and 82.9% of the isolates, respectively, at the breakpoint of

Doripenem is a broad-spectrum parenteral carbapenem recently approved in the United States for treatment of complicated urinary tract and intra-abdominal infections. Although pronounced doripenem antimicrobial activity against various Gram-negative pathogens, including anaerobes, has been confirmed, limited information has been forthcoming on the activity of this agent against leading Gram-positive species. We evaluated the activity of doripenem using reference broth microdilution procedures against a large collection of staphylococci, enterococci, and streptococci collected as part of a global (North America, 43.0%; Latin America, 11.7%; Europe, 31.3%; and Asia-Pacific, 14.0%) Doripenem Surveillance Program for the years 2003 to 2007. Doripenem was confirmed to be highly active against oxacillin-susceptible Staphylococcus aureus (22 389 isolates) and coagulase-negative staphylococci (2444 isolates; MIC(90) values

This study aimed to assess the peritoneal pharmacodynamics of intravenous doripenem using population pharmacokinetic modeling and Monte Carlo simulation. Drug concentrations in peritoneal fluid (PF) and serum from 11 laparotomy patients and MIC distributions against clinical isolates in Japan for 4 Gram-negative organisms were used. The probabilities of attaining the pharmacodynamic target (40% T > MIC) were greater in PF than in serum. To achieve a > or =90% probability of target attainment in PF, 0.25 g tid and 0.5 g tid (0.5-h infusions) had to be sufficient against Escherichia coli, Klebsiella spp., and Enterobacter cloacae; however, 1 g tid (0.5-h infusion) was required against Pseudomonas aeruginosa. Prolonged (4-h) infusion regimens resulted in increase of the target attainment probabilities in PF for P. aeruginosa. These results should help to achieve a better understanding of the peritoneal pharmacodynamics of doripenem while also helping to rationalize and optimize the dosing regimen for intra-abdominal infections.

Doripenem, a broad-spectrum parenteral carbapenem, has potency and pharmacokinetic/pharmacodynamic features most similar to imipenem and meropenem. Because of potential delays in release of commercial testing devices post-regulatory approval (US Food and Drug Administration), "surrogate markers" offer immediate susceptibility guidance for doripenem use. Cross-susceptibility analysis of reference MIC values compared imipenem, meropenem, and ertapenem with doripenem for 8 groupings of recent bacterial isolates (19308 strains). Use of proposed carbapenem or oxacillin surrogate testing agents until doripenem-containing commercial systems are available provides 89.1% to 100.0% absolute categorical agreement with

Doripenem (formerly S-4661), a novel carbapenem antimicrobial, was compared with ertapenem, imipenem, and meropenem using reference broth microdilution test methods against wild-type and various resistant microbial subsets (380 strains). Doripenem and meropenem were consistently more potent than ertapenem or imipenem when tested against Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. Ertapenem exhibited minimum inhibitory concentration (MIC) elevations for some isolates producing AmpC and extended-spectrum β-lactamases, in contrast to greater enzyme stability for doripenem and other carbapenems tested. Multiple β-lactamase (TEM, SHV, CTX-M, OXA, CMY types)–producing Escherichia coli had doripenem MIC values at ≤0.016 μg/mL (with higher values for ertapenem). Doripenem appears to be a promising, potent carbapenem for parenteral use against contemporary Gram-negative bacilli producing various β-lactamases.

We investigated the in vitro activities of carbapenems against 347 Streptococcus pneumoniae isolates from Korea. While doripenem and imipenem resistance was displayed by only 1.2% and 3.2%, respectively, 21.3% of the isolates were resistant to meropenem. One isolate displaying very high carbapenem MICs and susceptibility only to vancomycin was also identified.

At 24 h, sub-MIC doripenem and levofloxacin showed synergy against 21 of 25 Pseudomonas aeruginosa strains, sub-MIC doripenem and amikacin against 22 isolates, and sub-MIC doripenem and colistin against 19 isolates. Of 25 Acinetobacter baumannii strains, sub-MIC doripenem and levofloxacin showed synergy against 11 strains at 24 h, sub-MIC doripenem and amikacin against 24 strains, and sub-MIC doripenem and colistin against all isolates.

The emergence and rapid dissemination of extended-spectrum β-lactamase (ESBL)-producing isolates among Enterobacteriaceae coupled with increasing prevalence of stably derepressed and plasmid-borne AmpC producers have rendered broad-spectrum cephalosporins and β-lactam/β-lactamase inhibitor combinations less effective. This scenario has required the use of carbapenems for treatment of infections caused by such organisms. In this study, the in vitro activities of doripenem and comparator agents against Enterobacteriaceae, including ESBL- and AmpC-producing strains, were evaluated. A total of 36 614 isolates collected from more than 60 medical centers (2000–2007) were included and tested for susceptibility using reference methods and interpretive criteria, except for doripenem (product package insert). Overall, doripenem inhibited 98.7% of all Enterobacteriaceae tested at ≤0.5 μg/mL. ESBL rates were higher among Klebsiella pneumoniae (from 7.7% to 44.0%, varied by geographic region), followed by Escherichia coli (3.6–14.0%) and Proteus mirabilis (0.8–34.8%). Derepressed AmpC production-mediated resistance rates were highest among Enterobacter cloacae (26.6–38.7%) compared with other species and generally higher for strains isolated in the Asia-Pacific and Latin American regions. Doripenem inhibited 94.3% and 93.7% of the ESBL phenotype and derepressed AmpC isolates, respectively, and these resistances had little adverse influence on doripenem MIC 50 values (nil to 2-fold increases). The observed increase in AmpC- and ESBL-producing Enterobacteriaceae necessitates a greater confidence on carbapenem empiric therapy. Doripenem could represent a valuable choice for broad-spectrum coverage of contemporary Enterobacteriaceae isolates with widespread resistance mechanisms.

Doripenem, a synthetic 1-beta-methyl carbapenem, has a broad-spectrum of activity against almost all species of anaerobic bacteria, including all Bacteroides fragilis group species, most with MIC(90) results ator=1 microg/mL (with the exception of Sutterella wadsworthensis). Against Clostridium difficile strains, it has a narrow range of inhibitory concentrations (1-4 microg/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.

Doripenem (formerly S-4661), a parenteral carbapenem, was tested in combination with an aminoglycoside (gentamicin) to determine the resistance selection of these codrugs during subinhibitory passaging using 6 Pseudomonas aeruginosa isolates. The organisms were selected based on doripenem and gentamicin MIC values to include isolates with MIC values near the susceptible breakpoints of both compounds and 1 strain highly resistant to gentamicin. Baseline MIC values were established for doripenem (2-8 microg/mL) and gentamicin (4 to >256 microg/mL) using reference broth microdilution methods, and passaging was carried out over 7 consecutive days. Doripenem MIC values increased 2 to >/=8-fold in 4 isolates, whereas 2 strains maintained the baseline doripenem MIC. When the experiment was performed with doripenem plus gentamicin, 3 strains maintained the original doripenem MIC values, 2 strains had a 2-fold increase, and only 1 strain showed a 4-fold increase in the doripenem MIC values. Previous studies have demonstrated doripenem to be more potent than other members in its class when tested against P. aeruginosa. The combination of doripenem and an aminoglycoside may be an effective treatment of infections caused by P. aeruginosa with elevated carbapenem MIC values with lower risk of selecting further resistance.