Doripenem a Review of Its Use in the Treatment of Bacterial Infections

Drugs 2008; 68 (14): 2021-2057 ADIS DRUG EVALUATION 0012-6667/08/0014-2021/$53.45/0

Doripenem A Review of its Use in the Treatment of Bacterial Infections

Susan J. Keam Wolters Kluwer Health | Adis, Auckland, New Zealand, an editorial office of Wolters Kluwer Health, Conshohocken, Pennsylvania, USA

Various sections of the manuscript reviewed by: Y. Ike, Gunma University Graduate School of Medicine, Maebashi, Japan; T. Matsumoto, Department of Urology, University of Occupational and Environmental Health, Kitakyushu, Japan; G. Poulakou, 4th Department of Internal Medicine, Athens Medical School, Attikon University General Hospital, Athens, Greece; J.S. Solomkin, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA; F. Van Bambeke, Unite de Pharmacologie Cellulaire et Moleculaire, Universite Catholique de Louvain, Brussels, Belgium; G.G. Zhanel, Medical Microbiology Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada.

Data Selection Sources: Medical literature published in any language since 1980 on ‘doripenem’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘doripenem’. Searches were last updated 4 August 2008. Selection: Studies in patients with bacterial infections who received doripenem. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Doripenem, complicated intra-abdominal infections, complicated skin and skin structure infections, complicated urinary tract infections, nosocomial pneumonia, ventilator-associated pneumonia, gynaecological and obstetric infections, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

Contents

Summary ...... 2022 1. Introduction ...... 2025 2. Pharmacodynamic Profile ...... 2025 2.1 Mechanism of Action ...... 2025 2.2 In Vitro Antibacterial Activity ...... 2025 2.2.1 Gram-Negative Bacteria ...... 2027 2.2.2 Gram-Positive Bacteria ...... 2029 2.2.3 Anaerobic Bacteria ...... 2029 2.2.4 Synergistic Activity ...... 2031 2.2.5 Bactericidal Activity and Post-Antibiotic Effect ...... 2031 2.3 Resistance Issues ...... 2033 2.4 In Vivo Antibacterial Activity ...... 2035 2.5 Other Effects ...... 2035 3. Pharmacokinetic Properties ...... 2035 3.1 Distribution ...... 2035 3.2 Metabolism and Elimination ...... 2036 3.3 Special Patient Populations ...... 2036 3.3.1 In Renal Impairment ...... 2036 3.4 Potential Drug Interactions ...... 2037 2022 Keam

4. Pharmacodynamic/Pharmacokinetic Relationship ...... 2037 5. Therapeutic Efficacy ...... 2038 5.1 Serious Lower Respiratory Tract Infections ...... 2039 5.1.1 Nosocomial Pneumonia ...... 2041 5.2 Complicated Intra-Abdominal Infection ...... 2043 5.3 Complicated Urinary Tract Infection ...... 2044 5.4 Other Infections ...... 2046 5.4.1 Skin and Skin Structure Infections ...... 2046 5.4.2 Obstetric and Gynaecological Infection ...... 2046 5.4.3 Sepsis and Endocarditis ...... 2046 5.4.4 Ear, Nose and Throat Infections ...... 2047 5.4.5 Dental and Oral Surgical Infection ...... 2047 5.4.6 Ophthalmic Infection ...... 2047 6. Tolerability ...... 2047 7. Dosage and Administration ...... 2048 8. Place of Doripenem in the Management of Bacterial Infections ...... 2049

Summary Abstract Doripenem, a parenteral, broad-spectrum antibacterial agent of the carbapenem family, is indicated as empirical therapy in serious bacterial infections in adults. Doripenem is indicated in Japan for use as a single agent in intra-abdominal infections (IAIs), lower respiratory tract infections (including nosocomial pneumonia), complicated urinary tract infections (cUTIs) and a variety of other bacterial infections, such as complicated skin and skin structure infections (cSSSIs), obstetric and gynaecological infections, serious ear, nose and throat infections, sepsis and endocarditis, dental and oral surgical infection, and ophthalmic infection caused by various susceptible strains of Gram-negative, Gram-positive or anaerobic bacteria. Doripenem is indicated in the US for the treatment of complicated IAIs (cIAIs) or cUTIs, including pyelonephritis, caused by susceptible strains of designated pathogens, and in the EU for the treatment of nosocomial pneumonia (including ventilator-associated pneumonia [VAP]), cIAIs or cUTIs. Doripenem has a broad spectrum of in vitro activity against Gram-positive and Gram-negative bacteria, including extended-spectrum β-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae, and anaerobic pathogens. The drug also has a low propensity to select for resistance and is suitable for the prolonged infusions that may be required to achieve pharmacodynamic/pharmacokinetic targets for bactericidal activity (and therefore efficacy) against pathogens with increased MICs (minimum concentrations required to inhibit the pathogens). Doripenem is no less effective than other antibacterial agents, including meropenem, imipenem/ cilastin, piperacillin/tazobactam or levofloxacin in a wide range of serious bacterial infections, such as complicated lower respiratory infections, nosocomial pneumonia (including VAP), cIAIs and cUTIs, and is well tolerated. Thus, doripenem is a valuable addition to the options available for the empirical treatment of serious bacterial infections in hospitalized patients.

Pharmacological Doripenem demonstrated good in vitro activity against clinically relevant Enter- Properties obacteriaceae (Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella spp., Morganella morganii, Proteus spp. and Serratia spp.). The minimum concentration inhibiting 90% of strains (MIC90) was generally ≤0.5 mg/L and susceptibility rates were 93–100%. Doripenem was active against ESBL- and AmpC-producing Enterobacteriaceae, with little or no change in MIC90 values compared with non-ESBL- and non-AmpC-producing strains. Doripenem was also active against Haemophilus influenzae, Moraxella catarrhalis and Pro- videncia spp. (MIC90 ≤1.56 mg/L). Activity against non-fermentative Gram- negative pathogens was more limited. Doripenem MIC90 values were 0.2–12.5 mg/L against susceptible isolates of Pseudomonas aeruginosa and 8–64 mg/L against carbapenem- or ceftazidime-resistant isolates. Doripenem activity against Acinetobacter spp. was more limited in Europe and the Americas (MIC90 1–32 mg/L) than in Japan (MIC90 ≤3.13 mg/L). Doripenem demonstrated good in vitro activity against Gram-positive pathogens, including Staphylococcus aureus (methicillin/oxacillin-susceptible isolates), Streptococcus pneumoniae (including penicillin-, ceftriaxone- or multidrug-resistant strains), S. pyogenes and S. agalactiae (MIC90 ≤1 mg/L; susceptibility rate of 100%), but had limited activity against Enterococcus faecalis (MIC90 4–16 mg/L). Activity against S. epidermidis varied according to geographic region (e.g. for methicillin or oxacillin-susceptible isolates, MIC90 values were 0.03 mg/L in Europe and the Americas and ≤0.031–12.5 mg/L in Japan). Doripenem lacked activity against methicillin or oxacillin-resistant staphylococci and E. faecium. Doripenem demonstrated in vitro activity against a range of anaerobic pathogens, including B. fragilis, B. thetaiotaomicron and Prevotella spp. (MIC90 0.062–2 mg/L; susceptibility rates of 96–100%). Doripenem activity against Peptostreptococcus spp. varied (MIC90 0.063–6.25 mg/L). Doripenem has rapid, time-dependent bactericidal activity, a post-antibiotic effect of ≈2 hours against P. aeruginosa and S. aureus at 2 or 4 times the MIC, and no inoculum effect. Doripenem shows stability against hydrolysis by most β-lactamases, including ESBLs and AmpC β-lactamases, but may be affected by carbapenemases. How- ever, it is likely that in addition to carbapenemases, resistance mechanisms such as reduced permeability or overexpression of multidrug efflux pumps are required for significant carbapenem resistance to emerge. Doripenem appears to have a low potential for selecting resistant strains in vitro. Doripenem was generally at least as effective as meropenem/cilastin, imipenem/cilastin, biapenem, cefoxatime or cefpirome, and was more effective than ceftazidime, cefepime, ampicillin or piperacillin/tazobactam in various mouse or rat models of infection with clinically relevant Gram-negative, Gram-positive or anaerobic pathogens. Doripenem did not accumulate at steady state after intravenous administration. Plasma protein binding is low (≈8%) and the drug achieves good penetration into a wide range of tissues, including lung, intra-abdominal, dermal, and head and neck tissue, bone, and peritoneal fluid. Doripenem is mainly eliminated via the kidneys and clinically significant alterations to the pharmacokinetics of the drug are seen in patients with advanced or end-stage renal failure. Doripenem has a short plasma elimination half-life of ≈1 hour.

Mathematical models have estimated the simulated dosage regimen of doripenem that is likely to achieve an optimal bactericidal pharmacodynamic target attainment (unbound drug concentrations that are maintained above MIC for 30–40% of the dose administration interval). In one model, doripenem 250 or 500 mg administered over 30 minutes three times daily was predicted to be the optimal regimen against bacterial isolates with MICs of 1 or 2 mg/L and doripenem 250 mg twice daily was predicted to be optimal against bacterial isolates with MICs ≤0.5 mg/L. In another model, doripenem 500 mg administered over 60 minutes every 8 hours was predicted to be optimal against isolates with MICs ≤2 mg/L, while prolonged (4-hour) infusions of doripenem 500 mg every 8 hours or 1000 mg every 12 hours (MIC 4 mg/L) or 1000 mg every 8 hours (MIC 8 mg/L) were predicted to be optimal against isolates with higher MICs. An increase in dose administration frequency or duration of infusion, rather than dose per administration, was likely to prolong the period over which unbound doripenem concentrations exceeded the MIC. Therapeutic Efficacy The efficacy of intravenous doripenem in adult patients with serious bacterial infections has been examined in numerous randomized trials. Doripenem was not inferior to meropenem in Japanese patients with serious lower respiratory tract infection, achieving clinical response rates of >90% in either treatment arm, and bacteriological eradication rates of 86% and 96%, respectively. In two international trials in patients with nosocomial pneumonia (including VAP), doripenem was not inferior to imipenem/cilastin (clinical response rates of 57.8–68.3%) or piperacillin/tazobactam (clinical response rates of 64.1–81.3%) in the clinically evaluable and modified intent-to-treat populations. Bacteriological eradication rates across all treatment arms in these trials were 67.3–84.5%. Doripenem was not inferior to meropenem in two trials in patients with cIAIs. Clinical cure rates at the test-of-cure assessment were 74.5–85.9% with doripenem and 75.7–85.3% with meropenem. Microbiological cure rates were 84.3% with doripenem and 84.5% with meropenem when results of the two trials were combined. Doripenem was an effective alternative to meropenem or levofloxacin therapy in patients with cUTIs, evidenced by clinical response rates of 95–96% with doripenem, 89% with meropenem and 90% with levofloxacin. The respective bacteriological response rates were 82–96% for doripenem, 96% for meropenem and 83% for levofloxacin. A Japanese dose-finding trial in patients with cUTIs found that doripenem efficacy did not differ significantly between a 250 or 500 mg dose administered twice daily (clinical response rate of 97% in both treatment groups). Doripenem has also shown efficacy in small noncomparative Japanese studies in patients with cSSSIs, obstetric and gynaecological infection, sepsis and endocarditis, ear, nose and throat infections, dental and oral surgical infections, and ophthalmic infection (clinical and bacteriological response rates of 80–100%). Tolerability Intravenous doripenem was generally well tolerated in adult patients with serious bacterial infections, and most adverse events were mild to moderate in severity. The most commonly reported drug-related adverse events in patients treated with doripenem included headache, nausea and diarrhoea. The most commonly reported laboratory abnormalities included increased levels of ALT and AST. Doripen- em has good CNS tolerability, with no drug-related seizures reported in patients participating in clinical trials.

1. Introduction O OH

O The carbapenems are β-lactam antibacterial N agents with a broad spectrum of activity against a S H C wide range of Gram-positive and Gram-negative 3 aerobic bacteria, and against anaerobic bacteria. HH CH H NH OH 3 N 2 However, unlike other β-lactam antibacterials, N S H the carbapenems are stable to nearly all β- O O [1-3] lactamases. Consequently, in an age of increas- Fig. 1. Chemical structure of doripenem. ing resistance to antibacterial agents, carbapenems are an important therapeutic option, particularly in growth and ultimately leading to bacterial cell the treatment of serious infections.[1,2] The most death.[15] [1,2,4] widely available carbapenems are imipenem, Doripenem readily penetrates bacterial cell walls, [5-7] [8,9] meropenem and ertapenem. Doripenem binding with and deactivating specific penicillin- ® ™ 1 (Finibax , Doribax ), which has a spectrum of binding proteins (PBPs). PBPs 1a, 1b, 2 and 3 are of activity similar to that of imipenem and meropenem, primary importance because inhibition of these is the focus of this review. Other, less widely avail- PBPs leads to cell death.[15] In vitro, doripenem [10] able carbapenems include biapenem and panipe- shows strong affinity for PBPs 2, 3 and 4 in Pseudo- [11] nem. monas aeruginosa,[12,13,15,16] PBPs 2 and 4 in Es- This article reviews the pharmacological proper- cherichia coli[12,13,15,16] and PBP 1 in Staphylococcus ties of doripenem and its clinical efficacy and tolera- aureus[12,16] cell walls, with changes in cell morphol- bility as an intravenous agent in the treatment of ogy (e.g. formation of spherical cells due to inhibi- adults with lower respiratory tract infections (in- tion of PBP 2) apparent 1–2 hours after exposure to cluding nosocomial pneumonia), intra-abdominal the drug.[15,17] Doripenem is highly stable to hydrol- infections (IAIs), including complicated IAIs ysis by all serine β-lactamases, and is relatively (cIAIs), complicated urinary tract infections (cUTIs) stable to human recombinant dehydropeptidase-1 and a variety of other bacterial infections, such as (DHP-1),[16,18,19] unlike imipenem[1] or panipe- complicated skin and skin structure infections nem.[11] (cSSSIs), obstetric and gynaecological infections, serious ear, nose and throat (ENT) infections, sepsis 2.2 In Vitro Antibacterial Activity and endocarditis, dental and oral surgical infection, and ophthalmic infection. Doripenem is approved in The focus of this section is the in vitro activity of [12] doripenem against selected pathogens specified in a broad range of infections in Japan, for use in [13] [14] [12] cIAIs and cUTIs in the US[13] and EU,[14] and in the US, EU and Japanese manufacturer’s nosocomial pneumonia (including ventilator-asso- prescribing information (see table I for details). In ciated pneumonia [VAP]) in the EU.[14] the US, doripenem is indicated for the treatment of cIAI caused by E. coli, Klebsiella pneumoniae, P. aeruginosa, various Bacteroides spp., S. in- 2. Pharmacodynamic Profile termedius, S. constellatus and Peptostreptococcus micros, and for cUTI caused by E. coli, K. pneu- 2.1 Mechanism of Action moniae, Proteus mirabilis, P. aeruginosa and Acine- tobacter baumannii.[13] Doripenem is indicated in Doripenem (figure 1) is a carbapenem antibacter- adults for the treatment of nosocomial pneumonia ial agent with a broad spectrum of activity against (including VAP), cIAI and cUTI in the EU,[14] and in Gram-positive and Gram-negative bacteria and an- a wider range of indications in Japan, including aerobes.[3,15] Like other carbapenems, doripenem serious lower respiratory tract infections, IAI, cUTI, interferes with cell wall synthesis, inhibiting cell cSSSI, obstetric and gynaecological infections, seri-

1 The use of trade names is for product identification purposes only and does not imply endorsement.

Table I. Selected causative pathogens against which intravenous wide surveillance programmes (including the SEN- doripenem is indicated for the treatment of complicated intra-abdo- [20] [21] [20-32] minal infections or complicated urinary tract infections (US and TRY and TRUST programmes) and nu- EU),[13,14] nosocomial pneumonia (including ventilator-associated merous smaller studies (including phase III trials of pneumonia) [EU][14] and various serious infections in Japan[12] nosocomial pneumonia,[33,34] cIAIs[34,35] or cU- Organism Country TIs,[34,36] and a study in infected diabetic foot Gram-negative bacteria wounds[37]),[33-51] and between 1987 and 2006 in Acinetobacter spp. US (A. baumannii), EU,a Japan Japanese studies.[16,52-66] Some data are only avail- Citrobacter spp. EU, Japan able as abstracts and posters.[20-31,33-36,38,40,65] Enterobacter spp. EU, Japan Escherichia coli US, EU, Japan In vitro susceptibility testing was performed ac- Haemophilus influenzae EU, Japan cording to the Clinical and Laboratory Standards Klebsiella spp. US (K. pneumoniae), EU, Japan Institute (CLSI) methods for non-Japanese in vitro Moraxella catarrhalis Japan studies, and Japanese Chemotherapy Society or Morganella morganii EU, Japan CLSI methods for Japanese in vitro studies. CLSI Proteus spp. US (P. mirabilis), EU, Japan breakpoints for doripenem have not yet been estab- Providencia spp. EU, Japan lished; however, the following breakpoints, which Pseudomonas aeruginosa US, EU,a Japan are based on clinical outcomes, are proposed in the Serratia spp. EU, Japan US manufacturer’s prescribing information: Gram-positive bacteria ≤0.5 mg/L for Enterobacteriaceae, ≤2.0 mg/L for Enterococcus spp. EU (E. faecalis), Japan (except P. aeruginosa, ≤1.0 mg/L for A. baumannii, E. faecium) ≤ S. constellatus S. intermedius Staphylococcus spp. EU (methicillin-susceptible 0.12 mg/L for and , [13] strains), Japan (doripenem- and ≤1.0 mg/L for anaerobes; and in Brown and susceptible) Traczewski:[39] ≤2 mg/L for Enterobacteriaceae, Streptococcus pneumoniae EU, Japan non-fermentative Gram-negative bacilli, Staphylo- Streptococcus spp. US (S. constellatus, coccus spp. and H. influenzae, and ≤1 mg/L for S. intermedius), EU, Japan streptococci. In addition, some studies used a pro- Anaerobic bacteria posed breakpoint of ≤4.0 mg/L for establishing sus- Bacteroides spp. US and EU (B. caccae, [40,44,45,49,51,67] B. fragilis, B. thetaiotaomicron, ceptible organisms. As doripenem-re- B. uniformis, B. vulgatus), sistant isolates of these organisms have not yet been Japan identified, only susceptibility breakpoints are avail- Peptostreptococcus spp. US (P. micros), EU, Japan able in the US.[13,39] Jones et al.[68] have proposed the Prevotella spp. EU, Japan following possible carbapenem or other β-lactam a Acquired resistance may be a problem for A. baumannii and P. aeruginosa.[14] surrogate agents for doripenem susceptibility testing until doripenem-containing commercial systems are available: oxacillin for methicillin-susceptible S. au- ous ENT infections, sepsis and endocarditis, dental reus or coagulase-negative staphylococci; ampicil- and oral surgical infection, and ophthalmic infec- lin for enterococci; meropenem, imipenem or [12] tion. However, in the EU and Japan, specific ertapenem for Enterobacteriaceae; meropenem or organisms are not identified for each of these indica- imipenem for P. aeruginosa and Acinetobacter spp; [12,14] tions. Although the spectrum of doripenem an- and ertapenem for H. influenzae and S. pneumoniae. tibacterial activity includes numerous pathogens Recent European breakpoints proposed for doripen- other than those indicated, the efficacy and tolerabil- em are: ≤1 mg/L (susceptible) and >4 mg/L (resis- ity of the drug in infections due to these organisms tant) against Enterobacteriaceae, Acinetobacter spp. has not been established in well controlled clinical and Pseudomonas spp., and ≤1 mg/L (susceptible) trials, and the clinical significance of such activity is [13] and >1 mg/L (resistant) against Streptococcus spp., unclear. S. pneumoniae, Haemophilus spp. and anaerobes. Susceptibility data discussed in this section were Staphylococcal susceptibility and resistance is in- collected between 1997 and 2007 in large, world- ferred from the methicillin breakpoint.[14]

Comparator antibacterial agents shown in tables strains of H. influenzae was 2–3.13 mg/L (tables II II–IV were selected because they were the compara- and III). tor agents in the clinical trials discussed in section 5. Doripenem was active against P. aeruginosa isolates across all geographic areas (MIC90 2.2.1 Gram-Negative Bacteria 0.2–12.5 mg/L; tables II and III) [where evaluated, [26,45,51] Doripenem demonstrated good in vitro activity 87–100% susceptibility ], including ceftazi- [28] against clinically relevant Enterobacteriaceae, in- dime- or imipenem-susceptible or non-multidrug- [38] cluding E. coli, Klebsiella spp., Citrobacter spp., resistant isolates (MIC90 of 2–4 mg/L) obtained [38] [28] Enterobacter spp., Morganella morganii, Proteus from hospital inpatients in the US or Europe, spp. and Serratia spp. (tables II and III). The mini- and ceftazidime- or imipenem-susceptible or cef- mum concentration inhibiting 90% of strains tazidime-resistant Japanese isolates (including PER- 1-type ESBL-producing P. aeruginosa[52]) [MIC (MIC90) was generally ≤0.5 mg/L (tables II and III) 90 ≤ [52,58,63] and susceptibility rates, where reported, were 4 mg/L]. However, doripenem had poor ac- β 93–100%.[23,26,44,45,51] The exceptions were isolates tivity against metallo- -lactamase-producing or cef- from two Japanese studies[53,57] (one used isolates tazidime-, imipenem- or multidrug-resistant [53] P. aeruginosa isolates evidenced by MIC values from patients with cUTIs ) in which MIC90 values 90 were 1.56[57] and 3.13[53] mg/L against E. cloacae, of 8–64 mg/L (tables II and III) and, where reported, [40,51,67] 0.78[53] and 6.25[57] mg/L against P. vulgaris, 0.78 susceptibility rates of 22–40%. mg/L against P. mirabilis and M. morganii,[53] and Compared with activity against the parent wild- 6.25 mg/L against S. marcescens,[53,57] and two US type strain, doripenem activity was increased studies of selected clinical isolates[39,41] in which the against P. aeruginosa mutants lacking mexAB- MIC90 against P. mirabilis was 1 mg/L. oprM[58,62] (probably due to reduced expression of Doripenem showed good activity against extend- AmpC β-lactamase[62]), and virtually unchanged ed-spectrum β-lactamase (ESBL)-producing, Am- against mutant strains of P. aeruginosa (OprD defi- pC-producing (ceftazidime-intermediate/resis- ciency [reduced porin production] and over- tant), or fluoroquinolone-resistant Enterobacter- expression of mexAB-oprM or mexEF-oprN [in- iaceae.[20,23,29,32-34,36,41,44,47,51] For example, creased efflux pump activity]), with MIC90 values [58] doripenem MIC90 values did not differ between of 1.0 versus 0.5 mg/L. However, the activity of non-ESBL-producing and ESBL-producing E. coli, other carbapenems was reduced against strains that K. pneumoniae or P. mirabilis isolates (table II); had the combination of porin deficiency and in- however, in one Japanese study[59] the minimum creased efflux pump activity (by up to 4-fold for inhibitory concentration (MIC) was 32 mg/L against meropenem, up to 8-fold for imipenem and up to 16- one class B ESBL-producing strain of E. coli. fold for biapenem).[58] Doripenem also retained good antibacterial activity Doripenem showed limited activity against Aci- against both AmpC-producing and non-AmpC-pro- netobacter spp. (including A. baumanii) in studies in ducing strains of Enterobacter spp. and S. marces- Europe and the Americas, regardless of whether cens (MIC90 ≤0.5 vs ≤0.12 mg/L; susceptibility isolates were susceptible or ceftazidime-inter- [41,51] [41] rates of 100%). In one study, the MIC value mediate or -resistant (MIC90 1–32 mg/L; table II) was 2 mg/L against AmpC-producing P. mirabilis. [where reported, susceptibility rates 76–78%[26,45,51]] Doripenem activity against carbapenemase-pro- or carbapenemase- or metallo-β-lactamase-produc- ducing Klebsiella or Serratia spp. was limited, with ing (MICs 16–32 mg/L).[47] The MIC90 values for MIC90 values of 8 to >64 mg/L.[47] Acinetobacter spp. isolated in Japan were ≤3.13 mg/ Doripenem was active against the respiratory L (table III). pathogens H. influenzae and Moraxella catarrhalis The antibacterial activity of doripenem (MIC90 ≤1.56 mg/L), and against Providencia spp. against Gram-negative pathogens, including P. (MIC90 ≤1.56 mg/L), although the MIC90 for the β- aeruginosa and E. coli, was not affected by inocu- lactamase non-producing, ampicillin-resistant lum size.[16,70]

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (14) 2028 Keam e Continued next pag (Japanese studies are shown 23,44 23,41 20,23,32 39,41 32,45 41 44 41 32,45 39,41 References [24,28,29,31,33,35-41,44,45,48,51,67] 416 32 8–128 23,24,26,28,29,39,44,45 8–>128>128 23,28,29,36,39,41 >64 >64–>128≤ 1 41,44,51 ≤ 0.5– 1 25,27,32,45 ≤ 0.5–2 23,28,29,32,36,39,41,45 ≤ 1 2 4– ≥ 128 23-27,37,39,41,44,45 4–>64 20,23-27,32,37,39 >64–>128 24,25,27-29,39,51 32–>64>128 20,41,45 ≤ 1 4 >64–>128 20,23,32,41,44,51 4–128 28,29,32,39,44,45 4–>128 23,39,41 Testing was performed according to the Clinical and Laboratory ) 90 1 ≤ 0.5 >4–64 ≤ 0.03 LVX TZP 0.06 [28-30,41,44,51] and various smaller studies 2 1 ≤ 0.5–10.5 >4 ≥ 8–>32 >4 1 8 2–4 IPM 0.25–>8 8 0.25–0.5 [20-27,32] a ≤ 0.06–0.12 1 0.12 ≤ 0.03–0.12 0.25–10.12–0.25≤ 0.06–0.25 4 0.12–32 2–4 4–>128 28,29,35,36,39,41,45,51 ≤ 0.06–0.5 0.5–2≤ 0.06 >4 >8–>32 ≤ 0.12 0.25 ≤ 0.008 0.12 ≤ 0.015–0.06 0.25–0.5 0.25–8 2–128 20,23-29,32,35-37,39,41,45,51 MEM 1–>8 16 ≤ 0.06 programmes) [21] values (mg/L) 90 and TRUST [20] ≤ 0.06–0.5 0.06–0.5≤ 0.06–0.125 0.5–2 64 ≥ 8–32 ≤ 0.015–0.06 DOR ≤ 0.06–0.03 b 40 0.25 8831 0.06–0.12 0.5 0.06–0.12 0.25–1 10 0.5 38 0.5 619 0.25 426 0.25–0.5 0.12 141 0.03 959 0.03–0.06 0.03–0.12 0.12–2 2 567 1–16 886 291 0.03–0.12 0.03–0.06 1 1 410 0.12–0.5 0.06–0.5 1–4 1 625 0.03–0.25 2 052 0.12–1 3 9512 021 0.06–0.25 5 920 2 974 4 612 0.25–1 1 028 0.12 isolates 17 483 No. of Range of MIC c c c c c ESBL-producing CAZ-intermediate/resistant 438 0.25–0.5ESBL-producing 0.25 β -lactamase-producing CAZ-intermediate/resistant 19 2 IPM-resistant ESBL-producing CAZ-intermediate/resistant 10 >16 ESBL-producing Serratia spp. S. marcescens Other Acinetobacter spp. Escherichia coli K. pneumoniae Morganella morganii Proteus mirabilis Haemophilus influenzae Moraxella catarrhalis Table II. In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-negative bacteria. Data were collected between 1997 and 2007 in worldwide surveillance programmes (including the SENTRY Organism Enterobacteriaceae Citrobacter spp. Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC separately). Pathogens tested were clinical isolates, apart from drug-resistant pathogens in six studies. E. cloacae A. baumannii Providencia spp. Klebsiella spp. C. freundii Enterobacter spp.

2.2.2 Gram-Positive Bacteria Doripenem had good in vitro activity against the Gram-positive pathogens S. aureus or S. haemolyticus (methicillin- or oxacillin-suscepti-

≤ 2 for ble isolates), Streptococcus pneumoniae (including [39] ceftriaxone-resistant, penicillin-intermediate or -resistant or multidrug-resistant isolates), S. pyogenes and S. agalactiae, with MIC90 values of ≤1 mg/L across all geographic regions (tables IV and V) and, where reported, susceptibility rates of

References 100%.[25,27,44,45] However, S. epidermidis suscepti- [69] bility to doripenem varied according to geographic region, with MIC90 values of 0.03 mg/L (methicil- and Brown Traczewski: lin- or oxacillin-susceptible isolates) and 4 mg/L [13]

were also likely to be included in 2003–5 worldwide (oxacillin resistant) in Europe and the Americas >64–>128 21,28,40,44,51,67 [27] (table IV) compared with MIC90 values of ≤0.031–12.5 mg/L (methicillin susceptible) and 8–50 mg/L (methicillin resistant) in Japan (table V). 2–64 16–>128 20-22,24-29,31,32,35-37,39,45,48,51 LVX TZP As expected, doripenem did not demonstrate activity against methicillin- or oxacillin-resistant S. aureus (MIC90 8–64 mg/L) [tables IV and V]. Doripenem showed limited activity against Entero- coccus faecalis (MIC90 4–16 mg/L) and poor ac- 2–32 IPM tivity against other Enterococci, including E. faecium (MIC90 >32 to >128 mg/L) [table IV and table

a V]. The antibacterial activity of doripenem against Gram-positive pathogens, including S. aureus, was >8–>32 >8–128 128 1–16 MEM not affected by inoculum size.[16,70] values (mg/L) 90 IPM = imipenem; LVX levofloxacin; MEM meropenem; TZP piperacillin/tazobactam. 2.2.3 Anaerobic Bacteria Doripenem showed good activity against a range of anaerobic bacteria (tables VI and VII), although DOR regional variations in susceptibility were evident. For instance, doripenem MIC90 values against b B. fragilis isolates from Europe and the Americas

937 16–64 were 0.25–1 mg/L (susceptibility rates of CLSI breakpoints (mg/L) indicating susceptibility, intermediate susceptibility and resistance were ≤ 4, 8 ≥ 16 (MEM, IPM), 2, 4 isolates 11 990 0.5–>8 No. of Range of MIC [45,49] [14] 96–100% ), whereas MIC90 values against Jap- anese isolates were 0.78–2 mg/L (table VI and table Recent European breakpoints proposed for DOR are: ≤ 1 mg/L (susceptible) and >4 (resistant) against Enterobacteriaceae, Acinetobacter c

d VII). Likewise, for Peptostreptococcus spp., the results for both timeperiods are included.

[25] doripenem MIC90 was 0.25 mg/L against European and American isolates, and 0.063–6.25 mg/L against

[40,44,45,49,51,67] Japanese isolates (table VI and table VII). Doripenem also showed activity against toxigenic C. difficile clinical isolates (MIC90 2 mg/L); the manufacturer’s prescribing information: ≤ 0.5 for Enterobacteriaceae, 2.0 P. aeruginosa and 1.0 A. baumannii , spp. and Pseudomonas Enterobacteriaceae, non-fermentative Gram-negative bacilli and H. influenzae . Some studies used a proposed breakpoint of ≤ 4.0 mg/L for establishing susceptible organisms. (LVX), and ≤ 16/4, 32/4–64/4 ≥ 128/4 (TZP), apart from the TZP susceptibility breakpoint for P. aeruginosa , which was 64/4. surveillance data; P. aeruginosa isolates that were carbapenem or CAZ-nonsusceptible, metallo- β -lactamase-producing multidrug-resistant (including mucoid isolates). meropenem MIC90 against these isolates was also nonsusceptible isolates [42] Table II. Contd Organism Pseudomonas aeruginosa a CLSI breakpoints for DOR are not established; however, the following susceptibility (mg/L), which based on clinical outcomes, are proposed in the US b Although all isolates were tested against DOR, not comparators in any particular trial. c Isolates collected in Europe during 2003–5 and reported the 2003–6 European Surveillance programme results d CAZ = ceftazidime; ESBL extended-spectrum β -lactamase; 2 mg/L.

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (14) 2030 Keam Testing [16,53-58,61,63,65,66] References 16 16,53,61 58,63 58,63 16,55,57,61,63 16,53,61,63 16,53,57,61,63 16,53,55,57,61,63 55,57,61,63 16,61,65 16,61 16,53,61,63 16,53,55-57,61,65,66 and in Brown [69] [13] methods. Data shown are minimum [53,56,57,63] 0.25 1–1.56 BPM 1–8 32 0.5–1.56 16,53,61,63 1–6.25 2–3.13 2–12.5 0.5–6.25 16,53,61,63,65 16 4 1–6.25 4–25 CLSI breakpoints (mg/L) indicating susceptibility, [14] 0.5 PAM 16–32 32–64 1.56–2 6.25–8 1.56–2 0.39–1 25–32 or Japanese Society of Chemotherapy 1 IPM 2–16 16–32 0.78–3.130.39–3.13 0.39–1 0.39–1.56 0.125–3.13 16,53,55,57,61,63 0.39–3.130.2–1.56 0.2–0.5 0.25–0.78 0.125–1.56 16,55,57,61,63,66 1.56–6.253.13–12.5 0.78–-2 2–12.5 0.39–6.251.56–6.25 0.78–2 1.56–6.25 4–6.25 8–12.5 ≤ 0.03–0.1251–12.5 0.025–0.05 0.05–0.063 16,55,57,61,63 2–25 [16,54,55,58,61,65] a 0.063 MEM 2–8 16–32 ≤ 0.016–0.25 0.125–0.78 0.125–0.25 0.06–0.39 16,53-55,57,61,63,66 0.5–1.56 0.5–25 values (mg/L) 90 DOR ≤ 0.03–0.1 ) 90 b 43 0.063 90 2–3.13 isolates 183113 1–4 8–32 No. of Range of MIC 141137303 0.05–0.39500 0.1–0.39 0.063–3.13 0.032–0.39 0.1–0.39 0.05–6.25 0.2–3.13 0.2–0.25 0.125–1.56 53,61,63 175319235 0.05–0.1 0.05–0.2 0.25–0.78 0.031–0.1 0.03–0.1 0.063–0.78 2–6.25 180195313 0.2–0.78 0.25–6.25204 0.12–6.25224 0.05–0.2 0.39–0.78 0.78–3.13 0.125–6.25 0.5–1.56 0.78–6.25 0.5–12.5 0.25–1.56 0.5–6.25 1–25 103 0.39–0.5 0.0125–0.2 2–3.13 184139 0.025–0.031 0.2–1.56 <0.004–<0.03 0.1–1.56 534 1–12.5 c c ≤ 2 for Enterobacteriaceae, non-fermentative Gram-negative bacilli and H. influenzae . Recent European breakpoints proposed DOR are: 1 mg/L [39] proposed in the US manufacturer’s prescribing information: ≤ 0.5 for Enterobacteriaceae, 2.0 P. aeruginosa and 1.0 A. baumannii , intermediate susceptibility and resistance were ≤ 4, 8 ≥ 16 (MEM, IPM); CLSI breakpoints for PAM BPM have not been established. (susceptible) and >4 mg/L (resistant) against Enterobacteriaceae, Acinetobacter spp. Pseudomonas Traczewski: CAZ or IPM resistant BLNAR non-BLNAR CAZ or IPM susceptible was performed according to the Clinical and Laboratory Standards Institute (CLSI) Table III. In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-negative bacteria collected between 1987 2006 in Japan. concentrations inhibiting 90% of strains (MIC Organism Enterobacteriaceae Citrobacter spp. a Although CLSI breakpoints for doripenem have not yet been established, the following susceptibility (mg/L), which are based on clinical outcomes, b Although all isolates were tested against DOR, not comparators in any particular trial. c CAZ susceptible defined as MIC ≤ 8 mg/L; resistant ≥ 16 IPM 4 mg/L. BLNAR = β -lactamase non-producing ampicillin-resistant; BPM biapenem; CAZ ceftazidime; IPM imipenem; MEM meropenem; PAM panipenem. C. freundii E. cloacae Escherichia coli Enterobacter aerogenes Klebsiella oxytoca K. pneumoniae Morganella morganii Proteus mirabilis P. vulgaris Serratia marcescens Other Acinetobacter spp. Haemophilus influenzae Moraxella catarrhalis Providencia spp. Pseudomonas aeruginosa

Table IV. In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-positive bacteria. Data were collected between 1997 and 2007 in world-wide surveillance programmes[24-27,32] and various smaller studies[30,35-37,39,41,44,45] (Japanese studies are shown separately). Pathogens tested were clinical isolates, apart from drug-resistant pathogens in two studies.[30,41] Testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

Organism No. of Range of MIC90 values (mg/L)a References isolatesb DOR MEM IPM LVX TZP Enterococcus spp. 310 >32 >32 >8–>32 39,45 E. faecalis 141 4–16 8–16 2–4 2–32 4 35,36,41,45 E. faecium 21 >32 >32 >32 >64 41 Staphylococcus aureus c 12 724 0.03–≤0.06 0.12–0.125 0.03–≤0.5 ≤0.5 2 24-27,30,32,37,39,41,45 MRSA 1 391 8–32 8–>32 8–>32 >64–128 30,37,39,41 S. epidermidis 15 2 4 0.5 4 37 methicillin or oxacillin 39 0.03 0.06 ≤0.015 ≤141 susceptible oxacillin resistant 17 4 8 2 4 41 Streptococcus pneumoniae c 8 514 ≤0.008–1 ≤0.008–1 ≤0.008–1 1 ≤0.06 25-27,30,32,39,41,45 penicillin intermediate or 1 562 0.25–1 0.5–1 0.12–2 4–8 30,41,44,45 resistant multidrug resistant 57 1 1 ≤0.5 40 ceftriaxone resistant 11 1 44 a CLSI breakpoints for DOR are not established. Susceptibility breakpoints (mg/L) of ≤2 for Staphylococcus spp. and ≤1 for Streptococci have been proposed by Brown and Traczewski,[39] based on clinical outcomes. Other studies used a proposed breakpoint of ≤4.0 for establishing susceptible organisms.[40,44,45] Recent European breakpoints proposed for DOR are: ≤1 mg/L (susceptible) and >1 mg/L (resistant) against Streptococcus spp., S. pneumoniae and Haemophilus spp. Staphylococci susceptibility and resistance is inferred from the methicillin breakpoint.[14] CLSI breakpoints (mg/L) indicating susceptibility (S), intermediate susceptibility and resistance (R) were ≤4, 8 and ≥16 (MEM, IPM), ≤1, 2 and ≥4 (LVX), and ≤8/4 (S), ≥16/4 (R) [TZP] against Staphylococcus spp., ≤4 (S) [IPM], ≤2 (S) [LVX], and ≤1/4 (S), ≥2/4 (R) [TZP] against Haemophilus spp., ≤0.25, 0.5, ≥1 (MEM), ≤0.12, 0.25–0.5, ≥1 (IPM), ≤2, 4, ≥8 (LVX) against S. pneumoniae.[69] b Although all isolates were tested against DOR, not all isolates were tested against all comparators in any particular trial. c Isolates collected in Europe during 2003–5 and reported in the 2003–6 European Surveillance programme results[27] were also likely to be included in 2003–5 worldwide surveillance data;[25] results for both timeperiods are included. IPM = imipenem; LVX = levofloxacin; MEM = meropenem; MRSA = methicillin- or oxacillin-resistant S. aureus; TZP = piperacillin/ tazobactam.

2.2.4 Synergistic Activity MIC values against an IMP-2-producing Little antagonistic potential has been observed in A. baumanii strain were reduced from 16 mg/L to in vitro synergy tests with doripenem and amikacin, 1 mg/L for doripenem, 128 mg/L to 1 mg/L for cotrimoxazole, daptomycin, levofloxacin, linezolid, imipenem and >256 mg/L to 2 mg/L for mer- vancomycin, teicoplanin or ceftobiprole.[13,72-74] openem. Synergistic effects between the carbape- Preliminary data suggest a strong synergistic ef- nems and CP 3242 against VIM-1- or fect in vitro between the investigational metallo-β- VIM-2-producing P. aeruginosa strains were not as lactamase inhibitor CP 3242 and carbapenems, in- pronounced (MIC values were 0–16 times [VIM-1] cluding doripenem, against some carbapenemase- and 0–4 times [VIM-2] lower).[75] producing pathogens [reported as an abstract].[75] For instance, MIC values against an IMP-1-produc- 2.2.5 Bactericidal Activity and ing P. aeruginosa strain, which were 8 mg/L for Post-Antibiotic Effect doripenem and ≥256 mg/L for imipenem or mer- Doripenem exhibited rapid, time-dependent bac- openem, were reduced to 1 mg/L for doripenem and tericidal activity against P. aeruginosa (including 0.5 mg/L for imipenem or meropenem in the pres- an efflux pump over-expressing strain),[58,70,76] ence of 32 g/L of CP 3242 using broth dilution E. coli[70] and S. aureus.[70] For instance, a 3–4 log10 methods.[75] Likewise, in the presence of CP 3242, reduction in the P. aeruginosa bacterial count was

© 2008 Adis Data Information BV. All rights reserved. Drugs 2008; 68 (14) 2032 Keam Testing [16,53-55,57,63,65,66] CLSI breakpoints (mg/ methods. Data shown are [14] 16,53 References 16,53,57,63,65 16,53,55,57,63,65,66 57,66 53 57 53 53,54,63 16,53,63,65 [53,57,63] BPM 32–128 32–50 0.2 ≤ 0.016– 0.03 16,55,63 32–128 ≤ 0.006– 0.016 16,57,63 ≤ 0.031–0.05 0.032–0.125 16,53,55,57,63,66 1.56–6.25 8–16 PAM 32–128 16–25 ≤ 0.031–12.5 0.063–0.125 16,53,63 100 0.05 0.2 32–100 ≤ 0.006– 0.016 or Japanese Society of Chemotherapy CLSI breakpoints for PAM and BPM have not been established. [69] [16,54,55,65,66] 1–6.25 IPM 32–128 16–50 >100 0.1 0.2 16–128 0.125–0.5 0.063–0.125 0.25–0.5 16,55,63,65 ≤ 0.006– 0.016 a 8–25 MEM 16–100 16–50 100 0.2 16–100 ≤ 0.016–0.12 0.008– ≤ 0.03 <0.004– ≤ 0.016 3.13 0.5–1 ≤ 0.006– 0.016 values (mg/L) 90 ) 90 DOR ≤ 0.031–12.5 0.125–50 0.016–12.5 b 61 >64–100 >64–>100 >64–>100 >64–>100 64 54 100 40 0.2 78 0.008–0.06 54 0.78 256 4–12.5 isolates 121 64–>128322 64–>128 16–64 64–>128 64–>128 64–>128 16,57,63 No. of Range of MIC 104 16–25 114 195 8–50 105 0.025–0.625 0.063–0.125 0.016–0.25 0.016–0.025 0.032 100 0.25–1 131 <0.004– ≤ 0.016 based on clinical outcomes. Recent European breakpoints proposed for DOR are: ≤ 1 mg/L (susceptible) and >1 (resistant) against [39] Brown and Traczewski, L) indicating susceptibility (S), intermediate and resistance (R) were ≤ 4, 8 ≥ 16 (MEM, IPM) against Staphylococcus spp., 4 (S) [IPM] Haemophilus spp., ≤ 0.25, 0.5, ≥ 1 (MEM), 0.12, 0.25–0.5, (IPM) against S. pneumoniae . Streptococcus spp., S. pneumoniae and Haemophilus spp. Staphylococci susceptibility resistance is inferred from the methicillin breakpoint. MR MS MR MR MS MR E. faecalis E. faecium Staphylococcus aureus (MS) 209 0.06–0.1 0.12–0.39 0.025–0.1 Table V. In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-positive bacteria collected between 1987 2006 in Japan. Organism Enterococcus spp. a CLSI breakpoints for DOR have not been established. Susceptibility (mg/L) of ≤ 2 Staphylococcus spp and 1 Streptococci proposed by minimum concentrations inhibiting 90% of strains (MIC was generally performed according to the Clinical and Laboratory Standards Institute (CLSI) b Although all isolates were tested against DOR, not comparators in any particular trial. BPM = biapenem; IPM imipenem; MEM meropenem; MR methicillin, penicillin or oxacillin resistant; MS susceptible; PAM panipenem. S. epidermidis Streptococcus agalactiae S. pneumoniae S. haemolyticus (MS) S. pyogenes

observed over 6–8 hours with doripenem at 2–8 × quired by P. aeruginosa and other Gram-negative the MIC.[76] For most strains, killing was only slight- species.[78,79] Although carbapenemases are still un- ly more rapid and extensive at 8 × the MIC than at common, carbapenemase-producing Gram-negative 2 or 4 × the MIC.[76] The mean MBC : MIC ratio pathogens are being reported with increasing fre- against 20 clinical strains of P. aeruginosa was 1.5 quency.[78] for doripenem, 1.25 for meropenem and 1.7 for Other potential resistance mechanisms that can [58] imipenem, indicating strong bactericidal activity. confer resistance to β-lactam antibacterial drugs in- In contrast, the mean MBC : MIC ratio for ceftazi- clude alteration of PBPs leading to poor binding [58] dime was 2.45. affinity (present in bacteria such as Enterococcus Doripenem also showed bactericidal activity spp. and methicillin- or oxacillin-resistant S. aureus (99.9% kill) against various clinically relevant an- [MRSA]), overexpression of multidrug efflux aerobes (e.g. B. fragilis, B. thetaiotaomicron and pumps limiting drug accumulation at target sites × [43] P. intermedia) at 2 the MIC after 48 hours. (detected in some Gram-negative bacteria, including Doripenem demonstrated an in vitro post-antibi- P. aeruginosa[80-82] and B. fragilis[83,84]) and reduced otic effect (PAE) of 1.9 hours against S. aureus, membrane permeability due to loss of OprD, and 1.8–2 hours against P. aeruginosa, 0.3–0.5 hours thus a reduction in porins, in bacterial cell against E. coli and 0.3 hours against K. pneumoniae walls.[46,79,81,82] (all assessed at 2 or 4 × the MIC).[70,77] In in vitro studies, the loss of OprD in P. aerugi- 2.3 Resistance Issues nosa isolates increased doripenem, meropenem and imipenem MICs.[46] Increasing carbapenem resis- Doripenem shows stability against hydrolysis by tance in P. aeruginosa isolates as a result of the most β-lactamases, including AmpC β-lactamase overexpression of efflux pumps (including MexAB- and ESBLs.[16,32] As discussed in section 2.2.1, there OprM) has been documented;[80] doripenem and was little change in MIC90 values in comparisons of meropenem MICs were increased in such mutants, wild-type and ESBL-producing E. coli or K. pneu- whereas imipenem MICs were not affected.[46,80] moniae isolates, or wild-type and AmpC-producing Nevertheless, a combination of resistance mechan- Enterobacter spp. or S. marcescens.[32,51] However, isms, such as the presence of carbapenemases and carbapenemases can affect the activity of doripen- reduced permeability, or overexpression of mul- em.[78] Among the most potent carbapenemases are tidrug efflux pumps and reduced permeability, is the class B metallo-β-lactamases,[78] the production required for significant carbapenem resistance to of which is intrinsic in S. maltophilia, thus resulting emerge.[46,85] For example, detectable doripenem re- in resistance to doripenem,[32] but can also be ac- sistance in K. pneumoniae isolates[86] requires the

Table VI. In vitro activity of doripenem (DOR) and other antibacterials against anaerobic bacteria. Data were collected in various worldwide studies between 1997 and 2007.[37,43,45,49] Testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

Organism No. of Range of MIC90 values (mg/L)a References isolatesb DOR MEM IPM LVX TZP Bacteroides fragilis 222 0.25–1 0.25–1 0.125–0.5 2 0.25–1 37,43,45,49 B. thetaiotaomicron 74 0.5–1 0.5 0.5–1 8 16 43,49 Peptostreptococcus spp. 17 0.25 0.25 0.06 0.25 37 Prevotella spp. 91 0.062–0.5 0.062–0.25 0.03–0.25 0.5–8 ≤0.06 37,45,49 a CLSI breakpoints for DOR are not established; however, a susceptibility breakpoint of ≤1.0 mg/L for anaerobes is proposed in the US manufacturer’s prescribing information,[13] based on clinical outcomes. Some studies used a proposed breakpoint of ≤4.0 mg/L for establishing susceptible organisms.[45,49] Recent European breakpoints proposed for DOR against anaerobes are ≤1 mg/L (susceptible) and >1 mg/L (resistant).[14] CLSI breakpoints (mg/L) indicating susceptibility, intermediate susceptibility and resistance were ≤4, 8 and ≥16 (MEM, IPM) and ≤32/4, 64/4 and ≥128/4 (TZP); breakpoints for LVX were not available.[71] b Although all isolates were tested against DOR, not all isolates were tested against all comparators in any particular trial. IPM = imipenem; LVX = levofloxacin; MEM = meropenem; TZP = piperacillin/tazobactam.

Table VII. In vitro activity of doripenem (DOR) and other antibacterials against anaerobic bacteria isolated in Japan between 1987 and 2005.[16,54,60,63] Testing was generally performed according to the Clinical and Laboratory Standards Institute (CLSI)[16,54] or Japanese Society of Chemotherapy[60,63] methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

Organism No. of Range of MIC90 values (mg/L)a References isolatesb DOR MEM IPM PAM BPM Bacteroides spp. 56 0.78–8 0.78–8 0.78–8 8 1.56–16 16,60 B. distasonis 19 3.13 3.13 3.13 3.13 60 B. fragilis 130 0.78–2 0.39–2 0.39–2 0.5–2 0.78–2 54,60,63 B. thetaiotaomicron 34 0.78 0.78 0.39 0.78 60 Peptostreptococcus spp. 71 0.063–6.25 0.063–3.13 0.063–6.25 0.125–0.31 0.125–6.25 16,54,60 Prevotella spp. 118 0.1–1 0.1–1 0.1–2 0.125–1 0.125–0.39 16,54,60 a Although CLSI breakpoints for doripenem have not yet been established, a susceptibility breakpoint of ≤1.0 mg/L for anaerobes is proposed in the US manufacturer’s prescribing information,[13] based on clinical outcomes. Recent European breakpoints proposed for DOR against anaerobes are ≤1 mg/L (susceptible) and >1 mg/L (resistant).[14] CLSI breakpoints (mg/L) indicating susceptibility, intermediate susceptibility and resistance were ≤4, 8 and ≥16 (MEM, IPM); CLSI breakpoints for PAM and BPM have not been established.[71] b Although all isolates were tested against DOR, not all isolates were tested against all comparators in any particular trial. BPM = biapenem; IPM = imipenem; MEM = meropenem; PAM = panipenem. presence of both reduced permeability and the pres- P. aeruginosa isolates to subinhibitory concentra- ence of a carbapenemase, and reduced permeability tions of β-lactam antibacterials may increase al- and a functional AmpC β-lactamase are required for ginate production (and therefore reducing antibac- doripenem resistance in P. aeruginosa isolates[46] terial efficacy) by upregulating alginate-producing (see also section 2.2). Multiple resistance mechan- gene expression.[90] In planktonic cultures of wild- isms are also required for detectable meropenem type P. aeruginosa exposed to imipenem, doripen- resistance in P. aeruginosa isolates; in contrast, em or meropenem at concentrations 1 times the OprD loss alone may confer resistance to imipe- MIC, alginate biosynthetic operon expression and nem.[46] synthesis was generally unaffected by doripenem or In vitro studies in which characterized AmpC- meropenem, whereas with imipenem, alginate bio- inducible strains or wild-type clinical isolates of synthetic operon expression and synthesis was Enterobacteriaceae or P. aeruginosa were exposed upregulated (p < 0.01 for imipenem vs doripenem) to various antibacterial agents (including doripen- and flagellar gene expression was reduced.[91] Of em, meropenem or imipenem) at 0.5 or 1 times the interest, the response to imipenem was considered to MIC, revealed differences between the carbapenems be similar to the phenotype of mucoid strains of in inducing genes associated with resistance.[87,88] P. aeruginosa that are associated with increased For instance, imipenem induction of AmpC β- mortality in cystic fibrosis patients.[91] lactamases was at least 2-fold higher than that of Doripenem generally appears to have a low po- doripenem or meropenem, whereas doripenem and tential for selecting resistant strains in vi- [87,88] meropenem had similar induction profiles. In tro.[12,13,46,85,92] A study comparing the potencies of one of the studies, imipenem induction of porin gene doripenem, meropenem and imipenem in preventing expression was stronger than that seen with the emergence of carbapenem-resistant mutants of [87] doripenem. P. aeruginosa, found that mutants with decreased or Mucoid strains of P. aeruginosa (as opposed to no expression of the outer membrane protein OprD flagellar strains) produce large quantities of exo- were predominantly selected; relative potencies polysaccharide alginate, which is associated with were doripenem > imipenem > meropenem.[85] Seri- the evasion of phagocytosis at the site of infection, al passaging studies showed that the combination of protection against reactive oxygen intermediates doripenem plus an aminoglycoside (gentamicin) and reduced susceptibility to antibacterial agents.[89] was more potent than doripenem alone in preventing Various studies have suggested that exposure of selection of resistant P. aeruginosa strains during

the first three passages, although MIC values in- was 6.12 hours, compared with 5.9 and 3.49 hours creased 2- to 4-fold during the seven-passage for meropenem/cilastin or imipenem/cilastin 3 mg/ study.[92] Although potential exists for cross-resis- kg and 0.35 hours for ceftazidime 10 mg/kg.[58] tance to carbapenem-resistant isolates to develop (decreased susceptibility of S. aureus, E. coli and 2.5 Other Effects P. aeruginosa to doripenem, meropenem or imipe- Doripenem showed no convulsive activity in in nem with cross-resistance was seen in a serial pas- vivo studies in rats, mice or dogs, nor did it have an saging study [14 passages[16]]), some carbapenem- effect on the anticonvulsant activity of valproic acid resistant pathogens may be susceptible to doripen- in a rat pentylenetetrazol- or bicuculine-induced em.[12,13] convulsive model.[99]

2.4 In Vivo Antibacterial Activity 3. Pharmacokinetic Properties

In murine models of immunocompetent or neu- The pharmacokinetics of intravenous doripenem after single-[100-104] or multiple-[102,105] dose adminis- tropenic Gram-negative systemic, respiratory, UTI [105] [52,58,63,70,93-98] tration has been assessed in healthy US or Japa- or skin infection, or Gram-positive [102,103] [63,70,95] nese adult volunteers, in elderly Japa- systemic or lung infection, and rat models of [12,101] [13] [100] S. au- nese or US volunteers, and in US or penicillin-resistant pneumococcal meningitis, [12,104] reus endocarditis or polymicrobial intrauterine in- Japanese individuals with renal impairment. fection (E. coli and B. fragilis pyometra),[54] Tissue penetration of doripenem after intravenous administration has been assessed in a number of doripenem was generally at least as effective as [64,106-112] imipenem/cilastin, meropenem/cilastin, biapenem, studies in Japanese patients. Drug inter- cefotaxime or cefpirome, and more effective than action data for doripenem and valproic acid are from animal studies[113] and case reports.[114] Data from ceftazidime, cefepime, ampicillin or piperacillin/ta- [13] [14] [12] zobactam.[52,54,58,63,70,93-98] the US, EU and Japanese manufacturer’s prescribing information are supplemented by results Gram-negative organisms studied included [64,100-112] K. pneumoniae, P. vulgaris, H. influenzae (includ- from individual pharmacokinetic studies β or analyses,[115] and the manufacturer.[116] Some ing -lactamase-producing strains), P. aeruginosa [100,105,115] (including a PER-1-type ESBL-producing strain and data are only available as abstracts and ceftazidime-, imipenem- or multidrug-resistant posters. strains), A. calcoaceticus, wild-type or β-lactamase- 3.1 Distribution producing strains of E. coli, and ceftazidime-resistant strains of E. cloacae and S. marcescens. Gram- The pharmacokinetics of doripenem are linear positive organisms studied included S. aureus, S. py- over a dose range of 125–1000 mg, infused over ogenes, S. pneumoniae (including penicillin-resis- 30 or 60 minutes either as a single dose[102,115] or as a tant strains) and E. faecalis. Antibacterial activity 500 or 1000 mg dose administered two or three was assessed using the dose of drug resulting in the times daily for 1–7 days,[102,105] or over 4 hours[14] in survival of 50% of animals[52,58,63,70,93-95,97] or skin both Japanese[102] and non-Japanese[14,105,115] stud- lesion volume and/or bacterial cell count in flu- ies, with no evidence of accumulation. Plasma id.[54,63,95,98] doripenem concentrations are best described by a The effective bacterial regrowth time in a murine two-compartment model, according to a population neutropenic thigh infection model was 7.8 hours pharmacokinetic model that used data from healthy against S. aureus and 5 hours against K. pneumoniae adult volunteers (n = 24), individuals with renal after administration of doripenem 50 mg/kg and impairment (n = 20) and patients with cUTIs 8 hours against P. aeruginosa after a 100 mg/kg (n = 107).[115] Mean peak plasma concentration [77] dose. (Cmax) and area under the plasma concentration- In a neutropenic mouse P. aeruginosa lung infec- time curve (AUC) values after a single dose of tion model, the doripenem PAE after a 3 mg/kg dose doripenem 250 or 500 mg administered as a 1-hour

infusion in healthy non-Japanese or Japanese adults 3.2 Metabolism and Elimination are shown in table VIII. Doripenem is metabolized via DHP-1 to a micro- After prolonged (4-hour infusion) intravenous biologically inactive metabolite. Most of a dose of administration of doripenem 500 mg or 1 g in doripenem is not metabolized, as the drug is rela- healthy volunteers, mean Cmax values were ≈8 and tively stable to DHP-1.[13,14] In a study of prolonged- ≈17 μg/mL, and mean AUC values from time zero infusion regimens, the mean plasma doripenem me- to infinity were ≈34 and ≈68 μg • h/mL.[14] tabolite : doripenem AUC ratio was 13% after a Plasma protein binding of doripenem is low single dose of doripenem 500 mg administered over (≈8%) and is independent of plasma drug concentra- 4 hours and 18% after a single dose of doripenem [116] tions.[13,14] Doripenem distributes into a wide variety 1000 mg administered over 4 hours. In vitro studies have shown that doripenem does not under- of tissues, with a median volume of distribution (Vd) go metabolism by, and is therefore not a substrate at steady state of 16.8 L, consistent with distribution for, hepatic cytochrome P450 (CYP) isoenzymes. into the extracellular space.[13] Doripenem pene- During a period of 1 week after administration of a trates tissues well, and achieves drug concentrations single 500 mg dose of radiolabelled doripenem in at or above those required to inhibit most susceptible healthy volunteers, <1% of the total radioactivity bacteria, although the clinical significance of this was recovered in faeces.[13] finding in retroperitoneal fluid and peritoneal exu- Doripenem is primarily excreted as the un- [13] date is not established. After a single intravenous changed drug via the kidneys;[12,14] the high renal dose of 250 or 500 mg, doripenem concentrations clearance rate (table VIII) and the significant reduc- were detected in most tissues and/or fluids, includ- tion in doripenem elimination when the drug ing retroperitoneal fluid, peritoneal exudate, gall- coadministered with probenecid (section 3.4), sug- bladder tissue, bile, urine, dermal tissues, synovial gest that doripenem undergoes both active tubular fluid, bone, sputum, prostatic tissue, gynaecological secretion and glomerular filtration. Urinary elimina- tissues, middle ear mucosa and middle ear secretion is not dose dependent,[12] and 85–90% of a dose tions, palatine tonsil tissue, aqueous humour, gingi- is excreted (70–75% as the unchanged drug) within val tissue and various cysts.[12-14,64,106-112] Animal 24–48 hours of administration.[12,13] studies have shown that after intravenous administration, doripenem is also distributed extensively in 3.3 Special Patient Populations the kidney, liver, lung, heart and spleen.[117] The pharmacokinetics of intravenous doripenem are not affected by age, ethnicity or gender.[12-14] The Table VIII. Pharmacokinetics of intravenous doripenem (DOR) after effect of hepatic impairment on the pharmaco- a single 1-hour intravenous infusion of DOR 250 mg (n = 6)[12] or 500 mg (n = 6[12] and 24[13,14]) in healthy Japanese[12] or non-Japa- kinetics of doripenem has not been studied, but is nese[13,14] adults. Values are means, unless stated otherwise thought to be of no clinical consequence, because [13,14] Parameter DOR 250 mg[12] DOR 500 mg[12-14] the drug does not undergo hepatic metabolism. Cmax (μg/mL) 18.1a 23.0; 33.1a The pharmacokinetics of doripenem in patients with AUC12 (μg • h/mL) 20.26a 34.38;a 36.3b severe infections or sepsis are not available. Median Vd (L) 16.8c 3.3.1 In Renal Impairment CL (L/h) 15.9 As a result of prolongation of the doripenem CLR (L/h) 10.8 1 terminal elimination half-life (t /2β) in patients with 1 a a t 2β (h) 0.9 0.86; ≈1 / renal impairment,[12,100,104] systemic exposure to a In Japanese adults.[12] b AUC from time 0 to infinity. doripenem is significantly increased in these pa- [12-14,104] c At steady state. tients. In Japanese individuals, mean AUC values after intravenous administration of a single AUC12 = area under the plasma concentration-time curve from 1 time 0 to 12 h; Cmax = peak plasma concentration; CL = plasma 250 mg dose of doripenem, t /2β values in patients 1 β clearance; CLR = renal clearance; t /2 = terminal elimination half- with mild (creatinine clearance [CLCR] 50 to life; Vd = volume of distribution. <70 mL/min [3.0–4.2 L/h]), moderate (CLCR 30 to

<50 mL/min [1.8 to <3.0 L/h]) or severe (CLCR When carbapenems are administered concurrent- <30 mL/min [<1.8 L/h]) renal impairment were ly with valproic acid, serum valproic acid concentra- increased 2.2- to 4.0-fold compared with that in tions may be reduced to subtherapeutic levels with healthy volunteers (1.98, 2.16 and 3.56 vs 0.9 hours) subsequent loss of seizure control.[12-14] Consequent- and AUC values were increased 2.0- to 3.2-fold ly, coadministration of doripenem and valproic acid (40.55, 48.21 and 64.31 vs 20.26 μg • h/mL).[104] is contraindicated in Japan,[12] and requires frequent Likewise, in non-Japanese individuals, mean monitoring of serum valproic acid concentrations in AUC values after intravenous administration of a the US[13] and EU.[14] The mechanism of interaction single 500 mg dose of doripenem were increased is not understood, but results of animal and in vitro 1.6-fold in patients with mild renal impairment studies suggest that carbapenems may inhibit val- [113,114] (CLCR 50–79 mL/min [3.0–4.74 L/h]), 2.8-fold in proic acid glucuronide hydrolysis. those with moderate renal impairment (CLCR 31–50 mL/min [1.86–3.0 L/h]) and 5.1-fold in those 4. Pharmacodynamic/Pharmacokinetic Relationship with severe renal impairment (CLCR ≤30 mL/min [≤1.8 L/h]) compared with aged-matched individu- Animal models have shown that for time-depen- als with normal renal function.[13,14] Dosage adjust- dent antibacterials, such as the carbapenems, the ments are required in patients with moderate or pharmacodynamic/pharmacokinetic parameter that severe renal impairment (see section 7).[12-14] best correlates with bactericidal activity (and there- In patients with end-stage renal disease undergo- fore efficacy) is the proportion of the dose adminis- ing haemodialysis (doripenem was administered tration interval that unbound drug concentrations are post-dialysis), the mean doripenem AUC was in- maintained above the MIC (%T > MICfree).[118-120] A creased 7.8-fold compared with individuals with T > MICfree of 30–40% is thought to be sufficient normal renal function; 52% of a dose of doripenem for carbapenems,[118] including doripenem.[119,120] was recovered in dialysate (46% as the unchanged Murine neutropenic thigh infection models showed drug and 6% as the metabolite[116]) after a 4-hour that achieving a mean T > MICfree of 21–43% haemodialysis session.[13,116] Insufficient data are produced a 1 or 2 log reduction in bacterial count available for dosage adjustment recommendations for S. pneumoniae, S. aureus or Gram-negative ba- in this group of patients.[13] cilli (including ESBL-producing Enterobacter- iaceae).[120,121] A Monte Carlo simulation[120] used these 3.4 Potential Drug Interactions pharmacodynanamic/pharmacokinetic targets and a doripenem population pharmacokinetic model As doripenem is not metabolized via CYP iso- (based on pharmacokinetic data from 24 healthy enzymes (section 3.2), it is not expected to inhibit volunteers receiving a single intravenous 500 mg clearance of drugs metabolized via these pathways dose of doripenem [data are shown in table VIII]) as or to induce these isoenzymes in a clinically relevant inputs to identify potential doripenem dose adminis- manner.[13,14] tration regimens for phase II and phase III clinical When administered concomitantly with studies.[119] A regimen of doripenem 500 mg admin- probenecid, doripenem elimination decreased, evi- istered over 60 minutes every 8 hours was predicted 1 denced by a significantly prolonged t /2β (p = 0.0002 to be effective against bacterial isolates with MICs vs doripenem alone) and significant reductions in ≤2 mg/L, based on a 99–100% probability of achiev- systemic and renal clearance, and cumulative urin- ing a T > MICfree of 35% for doripenem MIC values ary excretion of doripenem (all p < 0.01).[103] As a of 1 or 2 mg/L.[119] For pathogens with an MIC of consequence, systemic exposure to doripenem >2 mg/L, prolonged (4-hour) infusions of doripen- (Cmax and AUC) was significantly increased em 500 mg every 8 hours or 1000 mg every 12 hours (both p < 0.01).[103] The concomitant administration (MIC 4 mg/L) or doripenem 1000 mg every 8 hours of doripenem and probenecid is not recommen- (MIC 8 mg/L) was predicted to be effective, based ded.[12-14] on a 100% probability of achieving a T > MICfree of

35%.[119] Prolonging the infusion duration increased occurred when T > MICfree was ≈20–30%. The the period over which doripenem concentrations simulated 4-hour infusion regimen was bactericidal exceeded MIC.[119] Estimates generated from a sim- for all P. aeruginosa isolates with an MIC ≤2 mg/L ulation predicting pharmacodynanamic/pharmaco- and for two of four isolates with MICs of 4 mg/ kinetic target attainment in individuals with normal L.[124] The option to administer doripenem as an or impaired renal function, using the same pharma- extended 4-hour infusion in patients with nosocomi- codynanamic/pharmacokinetic data were consistent al pneumonia (including VAP) in the EU prescrib- with these results.[122] ing information (section 7) is based on these re- In another murine neutropenic thigh infection sults.[14] model, a simulated regimen of doripenem 250 mg Although doripenem Cmax values in peritoneal twice daily infused over 30 minutes was bactericidal exudate were half those in serum after a single for E. coli, S. aureus and P. aeruginosa clinical 500 mg 30-minute intravenous fusion in ten patients isolates with MICs ≤0.5 mg/L.[123] This dosage regi- undergoing abdominal surgery (25 vs 47 mg/L), men achieved a T > MICfree of >35%, and bacterici- time to Cmax values in peritoneal exudate were dal activity did not increase significantly when the increased by 40% (0.7 vs 0.5 hours).[106] The mean T > MICfree increased to >40% (simulated treatment T > MICfree in peritoneal fluid was 78% for an MIC regimens of doripenem 500 mg twice daily or of 1 mg/L and 42% for an MIC of 4 mg/L, confirm- 250 mg three times daily infused over 30 minutes). ing that doripenem 500 mg every 8 hours was an Against P. aeruginosa strains with an MIC of 1 mg/ adequate treatment regimen to achieve bactericidal L, simulated regimens of doripenem 250 mg three activity against common pathogens associated with times daily or 500 mg twice daily administered over intra-abdominal infections[106] (e.g. E. coli [MIC90 30 minutes were required to achieve an adequate ≤0.015–0.1 mg/L; section 2.2.1], Streptococcus spp. T > MICfree (33–42%). [MIC90 ≤0.004–1 mg/L; section 2.2.2] and However, against P. aeruginosa strains with an B. fragilis [MIC90 0.25–2; section 2.2.3]). MIC of ≥2 mg/L, more frequent administration was A limitation of the Monte Carlo and other simula- necessary to achieve an adequate T > MICfree tions discussed in this section is that the pharmaco- value.[123] For instance, a simulated regimen of kinetic parameters were based on data from healthy doripenem 250 or 500 mg three times daily adminis- volunteers and may not apply to patient populations tered over 30 minutes achieved a T > MICfree of who have pharmacokinetics that differ significantly 31–38% against strains with an MIC of 2 mg/L, from those studied.[119,124] For instance, patients with whereas a simulated doripenem 500 mg twice-daily severe sepsis or septic shock have pharmacokinetic regimen only achieved a T > MICfree of 25%. profiles that differ markedly from healthy volun- Against strains with an MIC of 3 mg/L, a simulated teers or less critically ill patients, because of aggres- regimen of doripenem 500 mg three times daily sive fluid resuscitation, the loss of endothelial barri- administered over 30 minutes achieved a T > MIC- er function (capillary leak syndrome), renal or hep- free of 27%.[123] An increase in dose administration atic impairment and decreased tissue perfusion frequency, rather than dose per administration was resulting from impaired cardiocirculatory func- [125] associated with a more prolonged T > MICfree value tion. and greater bactericidal activity.[123] 5. Therapeutic Efficacy A murine neutropenic thigh model of P. aeruginosa infection was used to simulate the T > MICfree The therapeutic efficacy of doripenem in the value for a regimen of intravenous doripenem treatment of adult patients (mean age 50–59 years) 500 mg infused over 1 or 4 hours every 8 hours.[124] with lower respiratory tract infections (including The simulated 1-hour infusion regimen was bacteri- nosocomial pneumonia),[126-130] cIAIs[131-133] or cU- cidal for P. aeruginosa isolates with an MIC ≤2 mg/ TIs (including complicated or uncomplicated pyelo- L, but had variable kill for isolates with MICs of nephritis)[134,135] has been evaluated in eight ran- 4–8 mg/L. Bactericidal activity was maximal once domized, multicentre, phase II or III clinical studies. T > MICfree was ≥40% and bacteriostatic activity Several smaller, noncomparative studies in Japanese

patients with lower respiratory tract infections,[136] tazobactam in patients with nosocomial pneumo- IAIs,[107,136,137] cUTIs,[137-139] skin and skin structure nia[126,129] (one study only enrolled patients with infection,[112] obstetric and gynaecological infec- VAP[129]). Results of three small, noncomparative, tion,[108] sepsis and endocarditis,[140] ENT infec- Japanese studies of doripenem 250 mg two or three tion,[109,136] dental and oral surgery,[110] and oph- times daily, or 500 mg twice daily (in chronic thalmic infection[111] are also available. Three non- respiratory disease or community-acquired pneumo- Japanese studies[126,129,131] are fully published, and a nia [CAP])[136,137] and doripenem 500 mg two or further three[130,132,134] are only available as abstracts three times daily, 1 g twice daily or 500 mg twice and posters. All Japanese studies[107-112,127,128,136-140] daily titrated down to 250 mg twice daily based are fully published. on symptom improvement and age (in nosocomi- Primary efficacy endpoints in the randomized al pneumonia)[141] are also discussed briefly. Treat- trials related to clinical and/or microbiological res- ment duration varied between 3 and ponse rate, generally assessed at the test-of-cure 15 days.[126-129,136,137,141] visit.[126-129,131,132,134,135] Seven of the randomized In the two nonblind international trials (section studies[126,127,129,131,132,134,135] determined the nonin- 5.1.1), doripenem 500 mg three times daily[126,129] feriority of doripenem versus active comparators; (the trial in patients with VAP used a 4-hour rather however, only six studies specified the criterion for than the standard 1-hour infusion[129]) was compared noninferiority: a lower limit of the two-sided 95% with imipenem/cilastin 500 mg four times daily or confidence interval for the between-group differ- 1000 mg three times daily in one study,[129] or piper- ence in clinical[127,131,132,135] or microbiological[134] acillin/tazobactam 4.5 g four times daily in the other cure rate (doripenem minus active comparator) of study.[126] A pooled analysis of these data (available greater than or equal to –10%,[127,134,135] –15%[131,132] as an abstract)[130] and an assessment of hospital or –20%.[126,129] resource utilization in the comparison between The Japanese studies generally used doripenem and imipenem/cilastin[142] have been per- doripenem dosages of 250 mg twice[107-112,127,135-139] formed. Randomization in both trials was stratified or three times[107-111,128,136,137] daily, or 500 mg by geographic region,[126,129] disease severity (Acute twice[107-112,128,135-141] or three times[140,141] daily in- Physiology and Chronic Health Evaluation fused over 30–60 minutes. The other clinical studies [APACHE] II score ≤15 or >15),[126,129] the presence with doripenem utilized a dosage regimen of or absence of VAP[126] and/or the duration of 500 mg every 8 hours (infused over 60 min- mechanical ventilation (<5 or ≥5 days).[129] Both utes),[126,131,132,134] with the exception of one study in trials recommended coadministration of an amino- patients with nosocomial pneumonia in which glycoside[126,129] (amikacin[129]) [in suspected doripenem 500 mg every 8 hours was infused over P. aeruginosa infection] or vancomycin[126,129] (in 4 hours.[129] suspected MRSA infection) where required. Pa- tients in the study that compared doripenem with 5.1 Serious Lower Respiratory Tract Infections piperacillin/tazobactam[126] could be switched to The efficacy of intravenous doripenem in pa- oral levofloxacin 750 mg once daily after 3 days of tients with serious lower respiratory tract infections intravenous therapy (9 doses of doripenem and has been investigated in four randomized, multicen- 12 doses of piperacillin/tazobactam). tre trials:[126-129] a double-blind, Japanese, dose-find- Patients in the VAP study were required to meet ing study of doripenem 250 or 500 mg twice the clinical and radiological criteria for VAP, have a daily,[128] a double-blind, Japanese, noninferiority Clinical Pulmonary Infection Score of ≥5 and either comparison of doripenem 250 mg or meropenem have been mechanically ventilated for >24 hours or 500 mg twice daily[127] (both in patients with chronic weaned from mechanical ventilation within the pre- respiratory disease and concurrent, acute bacterial vious 24 hours.[129] At baseline in the clinically respiratory infection[127,128]) and two nonblind, inter- evaluable population (per-protocol evaluable; national, noninferiority trials comparisons of n = 248[129]), 48% of patients in the VAP study had doripenem versus imipenem/cilastin or piperacillin/ APACHE II scores ≤15, 10% of patients were

bacteraemic, 39% had early onset VAP (<5 days) gen that was susceptible or of intermediate suscepti- and 19% had renal impairment (CLCR <4.8 L/h bility to the study drug). [<80 mL/min]).[129] In the other study (n = 253 The most frequent causative pathogens isolated clinically evaluable patients),[126] 75% of patients at baseline were S. pneumoniae,[127-129,136] other had APACHE II scores ≤15, 10% of patients were Streptococcus spp.,[129] H. influenzae,[127-129] bacteraemic, 22% had early onset VAP (<5 days) P. aeruginosa,[126,129,136] S. aureus,[126,129] K. pneu- and 44%[126] had renal impairment (CLCR <4.8 L/h moniae[126,129] and E. cloacae.[126,129] In the random- [<80 mL/min]). ized trials of nosocomial pneumonia,[129] 13% of In the randomized, double-blind, Japanese trials, P. aeruginosa isolates were resistant to imipenem/ [129] clinical efficacy statistical analyses were primarily cilastin, while 27% of P. aeruginosa and 44% of conducted in the per-protocol population, supported K. pneumoniae isolates were resistant to piperacil- [126] by results in the modified intent-to-treat (mITT) lin/tazobactam. Few P. aeruginosa isolates [129] population.[127,128] In the noninferiority trial, only (none in the comparison with imipenem/cilastin patients with moderate, non-MRSA lower respira- and 8% in the comparison with piperacillin/tazobac- [126] [126] tory tract infection who complied with the treatment tam ) and no K. pneumoniae isolates were ≥ protocol were eligible for inclusion in the clinical resistant to doripenem. Most ( 64%) S. aureus iso- [126,129] efficacy per-protocol analysis (n = 96 doripenem lates were methicillin susceptible. and 97 meropenem recipients).[127] Chronic respira- A dose-finding trial found that doripenem tory disease included chronic bronchitis, bronchiec- 250 mg twice daily was the optimal dosage in Japa- tasis, asthma, emphysema, pulmonary fibrosis or nese patients with moderately severe chronic previous pulmonary tuberculosis.[127] Diagnoses in- respiratory infection.[128] Clinical efficacy rates with cluded bacterial pneumonia (n = 131) or chronic doripenem 250 mg twice daily or 500 mg twice daily respiratory disease with concurrent, acute respira- at the end-of-treatment (EOT) visit were 100% and tory infection (n = 62). Underlying disease or com- 88% in the per-protocol population (n = 36 and 34) plications were present in 85% of patients and 38% and 89% and 84% in the mITT population (n = 44 had already been treated with another antibacterial and 38); no significant between-group differences agent.[127] was evident. Likewise, there was no significant difference in bacterial eradication rates between the In all Japanese trials, clinical efficacy refers to two treatment groups (94.1% vs 89.5%; n = 17 and percentages of patients with ‘excellent’ or ‘good’ 19 evaluable patients).[128] clinical responses,[128,136,137] ‘clinical cure’[141] or ‘effective’ treatment.[127,128] Doripenem was not inferior to meropenem in the treatment of lower respiratory infections, according Co-primary efficacy endpoints in the nonblind, to results of a Japanese trial.[127] In patients with international trials were clinical cure rates at the CAP or chronic respiratory disease with acute infec- test-of-cure (TOC) visit (7–14 days after the cessa- tions, doripenem was noninferior to meropenem, [129] tion of therapy in the VAP study or 6–20 days with a clinical efficacy rate ≥90% (primary efficacy after the cessation of therapy in the comparison with endpoint; table IX). Results in the per-protocol pop- [126] piperacillin/tazobactam ) in the clinically evalu- ulation were supported by mITT analyses (full ana- [126,129] able and clinical mITT (patients who met the lysis set), in that clinical efficacy was evident in definition of the respiratory tract infection being 88.9% of doripenem (n = 108) and 86.8% of mer- studied and received any amount of the study drug openem (n = 106) recipients (between-group differ- [129] [126] [n = 501; n = 429 ]) populations. ence 2.1%; 95% CI –6.7, 10.9).[127] Bacteriological In all trials,[126-129,136,137,141] bacteriological res- eradication was seen in 86.0% of doripenem and ponse, which included eradication or presumed 95.8% of meropenem recipients. At the post-therapy eradication of pathogens isolated at baseline, was follow-up visit (n = 99), 11.4% of doripenem and assessed in the microbiologically evaluable popula- 7.3% of meropenem recipients had evidence of re- tion (defined in one trial[129] as the clinically evalu- current infection or re-infection.[127] When analysed able population who had at least one baseline patho- by diagnosis (CAP or chronic respiratory tract infec-

Table IX. Efficacy of intravenous doripenem (DOR) in serious bacterial lower respiratory tract infections. Results of randomized trials that compared DOR with imipenem/cilastin (IPM),[129] meropenem (MEM)[127] or piperacillin/tazobactam (TZP)[126] in patients (pts) with nosocomial pneumonia (including one trial[129] in pts with ventilator-associated pneumonia [VAP][126,129] or other serious lower respiratory tract infections.[127] Study drugs were administered intravenously Study No. of Treatment regimen Planned Response rates (% pts) [evaluable pts] pts treatment clinical between-group bacteriological between-group randomized duration response difference response difference (d) (95% CI) (95% CI) Nosocomial pneumonia, including VAP Chastre et 264 DOR 500 mg q8h infused 7–14 68.3a [126] 3.5 (–9.1, 16.1)b 73.3c [116] 6.0 (–6.8, 18.8) al.[129] over 4h 267 IPM 500 mg q6h or 7–14 64.8a [122] 67.3c [110] 1000 mg q8h infused over 30 or 60 min Rea-Neto´ et 225 DOR 500 mg q8h infused 7–14 81.3a [134] 1.5 (–9.1, 12.1)e 84.5c [84] 3.8 (–8.9, 16.5) al.[126] over 60 mind 223 TZP 4.5 g q6h infused 7–14 79.8a [119] 80.7c [83] over 30 mind

Other serious lower respiratory tract infections Saito et al.[127] 112 DOR 250 mg bid infused 7 92.7f [96] 2.0 (–5.8, 9.8)g 86.0 [43] –9.8 (–21.6, 2.0) over 30–60 min 107 MEM 500 mg bid infused 7 90.7f [97] 95.8 [48] over 30–60 min a Co-primary endpoint in the clinically evaluable population assessed at TOC visit 7–14 d[129] or 6–20 d[126] after completing treatment. b Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and IPM groups was greater than or equal to –20%. Noninferiority was also established in the clinical mITT analysis (n = 249 and 252; co- primary endpoint). c Assessed at TOC visit 7–14 d[129] or 6–20 d[126] after completing treatment. d Depending on response to treatment, pts could be switched to oral levofloxacin tablets (750 mg once daily) after a minimum of 3 days’ intravenous therapy with DOR (9 doses) or TZP (12 doses). e Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and TZP groups was greater than or equal to –20%. Noninferiority was also reported as being established in the clinical mITT analysis (n = 213 and 209; co-primary endpoint). f Primary efficacy endpoint in the per-protocol population. g Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and MEM groups was greater than or equal to –10%. bid = twice daily; mITT = modified intent-to-treat; qxh = every x hours; TOC = test of cure. tion), the presence or absence of underlying disease 5.1.1 Nosocomial Pneumonia or complicating factors, or previous antibacterial Doripenem was not inferior to imipenem/cilas- therapy, clinical efficacy rates were ≥89% and did tin[129] or piperacillin/tazobactam[126] in patients not differ between doripenem or meropenem.[127] with nosocomial pneumonia, including those with VAP. Clinical cure rates with doripenem at the TOC In patients with chronic respiratory tract infection visit were noninferior to those with either compara- or CAP and other pulmonary infection (n = 102[136] tor in both the clinically evaluable (table IX) and and 41[137]) that were included in two noncompara- clinical mITT populations. In the latter analyses, a tive trials of mixed infections, doripenem 125 mg clinical cure was seen in 59.0% of doripenem and twice daily, 250 mg two or three times daily or 57.8% of imipenem/cilastin recipients with VAP (between-group difference 1.2%; 95% CI –7.9, 500 mg twice daily achieved clinical response rates 10.3),[129] and 69.5% of doripenem and 64.1% of of 85–95% at treatment end and bacteriological piperacillin/tazobactam recipients with nosocomial eradication rates of 86–100%.[136,137] pneumonia (between-group difference 5.4%; 95%

DOR CI –4.1, 14.8).[126] Combined clinical cure rates in a TZP 11 15 the microbiologically evaluable population at the 100 14 TOC visit were 74.5% with doripenem (n = 200) and 90 6 18 80 14 70.5% with the comparators (imipenem/cilastin or 17 piperacillin/tazobactam) [n = 193].[130] 70 11 60 Patients receiving doripenem (n = 249) experi- 50 enced a significantly shorter median hospital length 40 of stay (22 vs 27 days; p = 0.01) and duration of 30 mechanical ventilation (7 vs 10 days; p = 0.03) than 20

Microbiological cure rate (%) 10 imipenem/cilastin recipients (n = 250), although 0 length of stay in the intensive care unit with either treatment did not differ (median of 12 vs 13 days) MSSA [clinical mITT analysis].[142] cloacae Klebsiella Enterobacter pneumoniae Pseudomonasaeruginosa Subgroup analyses showed that doripenem maintained good efficacy in higher risk patient sub- groups. For instance, clinical cure rates were ≥57% b with doripenem,[126,129] imipenem/cilastin[129] or piperacillin/tazobactam[126] in patients with 100 DOR 90 IPM nosocomial pneumonia (including VAP) who were 37 32 15 ≥ [126,129] 80 16 12 elderly (aged 65 years) or had APACHE II 10 17 21 70 20 scores >15[126] or >20.[129] 17 10 60 Microbiological cure rates with doripenem, imi- 50 penem/cilastin or piperacillin/tazobactam in the mi- 40 14 ≥ 30 crobiologically evaluable population were 67% [126,129] 20 (table IX). Pooled results in the microbiologi- Microbiological cure rate (%) 10 cally evaluable population showed that the microbi- 0 ological cure rate was 78.0% (156 of 200 patients) with doripenem and 73.1% (141 of 193 patients) MSSA with imipenem/cilastin or piperacillin/tazobactam cloacae Klebsiella Enterobacter Haemophilusinfluenzae and per-pathogen eradication rates with doripenem Eschericia coli pneumoniae Pseudomonasaeruginosa were ≥74%.[130] Microbiological cure rates by selected bacterial pathogen from the two clinical [126,129] Fig. 2. Efficacy of intravenous doripenem (DOR) in patients with trials are shown in figure 2. In patients with ventilator-associated pneumonia (VAP) or nosocomial pneumonia. P. aeruginosa, K. pneumoniae or E. coli infections Microbiological response rates by pathogen in the microbiologically evaluable population in two randomized, open-label, multicentre at baseline in the VAP study, microbiological cure clinical trials comparing DOR with (a) piperacillin/tazobactam rates were numerically higher with doripenem than (TZP)[126] and (b) imipenem/cilastin (IPM).[129] Adult patients re- imipenem/cilastin (figure 2); however, the number ceived DOR 500 mg every 8 hours[126,129] (infused over 4 hours, rather than the standard 1 hour, in the trial in patients with VAP[129]), of isolates in each comparison were small and be- TZP 4.5 g every 6 hours[126] or IMP 500 mg every 6 hours, or 1000 tween-treatment differences were not statistically mg every 8 hours[129] for 7–14 days. Where reported,[129] eligible significant.[129] patients had a measurable outcome at the test-of-cure visit and at least one baseline pathogen susceptible (or of intermediate sus- A clinical cure was achieved in 13 of 14 evalu- ceptibility) to the study drug. Microbiological cure was usually de- able patients with nosocomial pneumonia who re- fined as eradication or presumed eradication.[129] The number of patients in whom the individual pathogens were isolated at baseline ceived doripenem 1–2 g/day as divided doses two or are shown above each bar. MSSA = methicillin-susceptible three times daily for 8–13 days in a small Japanese Staphylococcus aureus. trial.[141]

Table X. Efficacy of intravenous doripenem (DOR) in complicated intra-abdominal infection. Results of two randomized, double-blind, double-dummy, multicentre trials that compared DOR with meropenem (MEM).[131,132,135] Planned treatment duration was 5–14 days. DOR and MEM were administered intravenously and patients (pts) could be switched to oral amoxicillin/clavulanic acid after at least nine doses of DOR or MEM. One study reported as an abstract and poster[132] Study No. of pts Treatment regimen Clinical response (% pts) [evaluable pts] randomized EOT TOC Lucasti et al.[131] 237 DOR 500 mg q8h infusion over 60 min 94.5 [163] 85.9 [163]a,b 239 MEM 1 g q8h bolus over 3–5 min 94.2 [156] 85.3 [156]a Malafaia et al.[132] 242 DOR 500 mg q8h infusion over 60 min 83.3 [162]a,c 233 MEM 1 g q8h bolus over 3–5 min 83.0 [153]a a Co-primary endpoint in the microbiologically evaluable population at follow-up 21–60 d[131] or 28–42 d[132] after the last dose of study drug (DOR or MEM alone, or DOR or MEM then oral therapy). b Between-group difference of 0.6% (95% CI –7.7, 9.0). Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and MEM groups was greater than or equal to –15%. Noninferiority was also established in the mITT analysis (n = 195 and 190; co-primary endpoint). c Between-group difference of 0.3% (95% CI –8.6, 9.2). Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and MEM groups was greater than or equal to –15%. Noninferiority was also established in the mITT analysis (n = 200 and 185; co-primary endpoint). EOT = end-of-treatment; mITT = modified intent-to-treat; qxh = every x hours; TOC = test of cure.

5.2 Complicated Intra-Abdominal Infection logical mITT (mMITT) population up to 60 days after the last dose of the study drug.[131,132] The efficacy of intravenous doripenem 500 mg Doripenem was not inferior to meropenem in the three times daily was compared with that of intrave- treatment of cIAI.[131,132] Clinical cure rates at the nous meropenem 1000 mg three times daily in two TOC assessment were ≥75%, and outcomes with randomized, double-blind, double-dummy, noninfe- doripenem were noninferior to those with mer- riority trials in patients with cIAIs requiring paren- openem in both the microbiologically evaluable teral antibacterial therapy (one fully published[131] (table X) and the mMITT (co-primary endpoints) and the other[132] reported as an abstract and poster). patient populations (77.9% vs 78.9%, between- An analysis of the combined results of these two group difference –1.0% [95% CI –9.7, 7.7] in one [131] studies (reported as an abstract and poster)[133] is study; and 74.5% vs 75.7%, between-group dif- – – [132] also available. The duration of study therapy was a ference 1.2% [95% CI 10.3, 8.0] in the other ). The mMITT patient population included 195[131] and minimum of 5 days and a maximum of 14 days; [132] [131] however, patients could be switched to oral amox- 200 doripenem recipients and 190 and 185[132] meropenem recipients. Doripenem showed icillin/clavulanic acid after at least nine doses of good bacterial eradication rates for organisms asso- doripenem or meropenem.[132] Randomization was ciated with cIAIs, including Enterobacteriaceae, stratified by geographic region, and within each P. aeruginosa and viridans Streptococci region, by primary site of infection (localized ap- group;[131,132] for instance, eradication rates with pendicitis vs other sites of IAI) and by severity of doripenem or meropenem for E. coli were 87.5% ≤ [131-133] illness (APACHE II score 10 or >10). E. coli and 84.0% (between-group difference 3.5%; 95% was the most frequently isolated pathogen at base- CI not reported) in one study[131] and 87.5% and [131,132] line. 84.8% (between-group difference 2.7; 95% CI –7.6, The co-primary efficacy endpoints were clinical 13.0) in the other.[132] response at the TOC visit 21–60 days after complet- An analysis of combined results from these two ing treatment with the study drug (intravenous trials confirmed the noninferiority of doripenem to doripenem or meropenem alone or doripenem or meropenem in cIAI.[133] Clinical cure rates in the meropenem followed by oral amoxicillin/clavulanic microbiologically evaluable population at EOT was acid therapy) in the microbiologically evaluable 84.6% for doripenem (n = 325) and 84.1% for population and clinical response in the the microbio- meropenem (n = 309) [between-group difference

0.5%; 95% CI –5.5, 6.4], while those in the mMITT ceived only intravenous therapy (11% of doripenem population were 76.2% (n = 395) and 77.3% and 18% of levofloxacin recipients) for the treat- (n = 375), respectively (between-group difference ment duration.[134] [133] –1.1%; 95% CI –7.4, 5.1). A microbiological Inclusion criteria in the Japanese trial were pyu- cure was achieved in 84.3% of doripenem and ria of at least five white blood cells per high-power 84.5% of meropenem recipients in the microbiologi- ≥ 4 [133] field and bacteriuria of 10 CFU/mL, and identifi- cally evaluable population. Bacterial eradication able underlying urinary tract disease.[135] Most pa- rates with doripenem or meropenem were 88% and tients were male (72% of the per-protocol popula- 84% for E. coli, 78% and 95% for K. pneumoniae, tion [n = 155]) and ≥75% were aged 60–80 84% and 79% for B. fragilis, and 85% and 75% for years.[135] At baseline, ≈50% of patients were diag- P. aeruginosa.[133] nosed with cystitis[135] and ≈50% were diagnosed Two small, noncomparative trials (n = 48 and with pyelonephritis.[135] Renal function was normal n = 15) in Japanese patients with IAI (including in 83% of patients in the Japanese trial.[135] Patients patients with cholecystitis, cholangitis and hepatic were included in the trial in non-Japanese patients if abscesses) found that intravenous doripenem a clinical and microbiological diagnosis of cUTI 250 mg two or three times daily, or 500 mg twice (complicated lower UTI [cLUTI], or complicated or daily for 3–14 days achieved clinical response rates uncomplicated pyelonephritis) was made.[134] Most (assessed as ‘excellent’ or ‘good’ clinical responses) patients were female (61% of 545 microbiologically of 90% and 100%, and bacterial eradication rates of evaluable patients) and ≈36% of patients were aged 61% and 55%.[107] The most common pathogens ≥65 years.[134] At baseline, ≈50% of patients were isolated at baseline were P. aeruginosa, K. pneu- diagnosed with cLUTI[134] and ≈50% were diag- moniae, E. faecalis, E. coli and B. fragilis.[107] nosed with pyelonephritis (severe in 9% of pa- [134] 5.3 Complicated Urinary Tract Infection tients). Renal function was normal or mildly impaired (CLCR ≥3.0 L/h) in 87% of patients.[134] The efficacy of intravenous doripenem 250 mg E. coli was the most frequent pathogen isolated at twice daily was compared with that of intravenous baseline in both studies;[134,135] other organisms iso- meropenem 500 mg twice daily in a Japanese ran- lated included E. faecalis, P. aeruginosa, K. pneu- domized, double-blind trial in adult patients with moniae, S. epidermidis, S. marcescens and cUTIs requiring parenteral antibacterial therapy.[135] P. mirabilis. Intravenous doripenem or meropenem was administered for 5 days in this trial.[135] In another trial (in Both trials were noninferiority studies in which non-Japanese adult patients with cUTIs requiring the noninferiority of doripenem to the comparator parenteral antibacterial therapy), doripenem 500 mg drug was established if the lower limit of the 95% CI three times daily infused over 30–60 minutes was for the difference in the rates of microbiological compared with levofloxacin 250 mg once daily (re- cure[134] or overall clinical efficacy[135] between the ported as an abstract and poster).[134] This trial was two treatment groups was greater than or equal to randomized, double-blind and double-dummy in de- –10%. The primary efficacy endpoint in the Japa- sign, and the planned duration of treatment was nese trial was overall clinical efficacy (classed as 10 days.[134] Patients could be switched to oral ‘excellent’, ‘moderate’ or ‘poor’, according to crite- levofloxacin tablets (250 mg once daily) after a ria proposed by the Japanese UTI Committee in the minimum of 3 days intravenous therapy (nine doses per-protocol patient population). The per-protocol of doripenem). The actual treatment duration was a population was defined as patients who met the mean 9.5 days in the doripenem arm and 9.1 days in protocol-specified disease definition of cUTI, who the levofloxacin arm (intent-to-treat analysis). Pa- had an interpretable urine culture at baseline and at tients received a mean 5.4 days of intravenous the efficacy assessment visit, and who had no entry doripenem or 5.3 days of intravenous levofloxacin criteria or protocol violation during treatment that before switching to oral levofloxacin (mean of was likely to affect the microbiological outcome. ≈6 days’ treatment).[134] A minority of patients re- Secondary endpoints included bacteriological res-

Table XI. Efficacy of intravenous doripenem (DOR) in complicated urinary tract infection. Results of two randomized, double-blind, multicentre trials that compared DOR with meropenem (MEM)[135] or levofloxacin (LVX).[134] Study drugs were administered intravenously (IV). One study was available only as an abstract and poster.[134] Response was assessed at the test-of-cure (TOC) visit Study No. of pts Treatment regimen Planned [mean Clinical Bacteriological randomized actual] treatment response (% pts) response (% pts) duration (d) [evaluable pts] [evaluable pts] Kamidono et al.[135] 96 DOR 250 mg bid infusion over 30–60 min 5 96.1a,b [76] 95.9b,c [98] 107 MEM 500 mg bid infusion over 30–60 min 5 88.6a [79] 96.2c [105] Naber et al.[134] 376 DOR 500 mg q8h infusion over 60 mind 10 [9.5] 95.1e,f [286] 82.1g,h [280] 372 LVX 250 mg q24h infusion over 60 mind 10 [9.1] 90.2e [266] 83.4g [265] a Primary efficacy endpoint in the per-protocol population. b Between-group difference not reported. Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and MEM groups was greater than or equal to –10%. c Percentage of strains [no. of strains]. d Depending on response to treatment, patients could be switched to oral LVX tablets (250 mg once daily) after a minimum of 3 days’ intravenous therapy (nine doses of DOR or three doses of LVX). e In the clinically evaluable population. f Between-group difference 4.9% (95% CI 0.2, 9.6). g Co-primary endpoint in the microbiologically evaluable population at TOC visit 6–11 d after the last dose of study drug (IV DOR or LVX alone, or IV DOR or LVX then oral LVX). h Between-group difference of –1.3% (95% CI –8.0, 5.5). Noninferiority was established in that the lower limit of the 95% CI for the difference in response rates between the DOR and LVX groups was greater than or equal to –10%. Noninferiority was also established in the mMITT population (n = 327 and 321; co-primary endpoint); microbiological cure rates were 79.2% vs 78.2% (between-group difference 1.0%; 95% CI –5.6, 7.6). bid = twice daily; mMITT = microbiological modified intent-to-treat; pts = patients; qxh = every x hours. ponse, defined as the percentage of bacterial strains criteria for the microbiologically evaluable popula- eradicated or presumed eradicated.[135] tion but were required to have a clinical outcome assessment, rather than an interpretable urine cul- The co-primary efficacy endpoints in the other ture, at the TOC visit).[134] trial were microbiological cure rate (eradication of baseline pathogens [<104 CFU/mL]) at the TOC Doripenem was not inferior to meropenem[135] or visit (6–11 days after completing study drug ther- levofloxacin[134] in two trials in patients with cUTIs. apy) in the microbiologically evaluable and mMITT At the TOC visit, clinical response rates with populations.[134] The microbiologically evaluable doripenem or meropenem were ≥88% in the per- population was defined as patients who met the protocol population in the Japanese trial[135] (prima- protocol-specified disease definition of cUTI, who ry endpoint; table XI). The bacteriological response had a study-qualifying pre-treatment urine culture rate with doripenem was noninferior to that with (at least one, but no more than two bacterial meropenem in the Japanese trial (table XI; between- uropathogens each at ≥105 CFU/mL) and an inter- group difference and 95% confidence intervals not pretable urine culture at the TOC visit, and who had reported), as were clinical efficacy rates judged by no entry criteria or protocol violation during treat- the attending urologist (93.4% vs 92.4% [between- ment that was likely to affect the microbiological group difference and 95% confidence intervals not outcome. The mMITT population included all ran- reported]).[135] Bacterial eradication rates with either domized patients who received at least a partial dose agent for Gram-negative or Gram-positive patho- of study therapy and had a study-qualifying pre- gens were >95%.[135] treatment urine culture.[134] Secondary endpoints in- In the trial in non-Japanese patients, microbio- cluded the microbiological cure rate in microbiolog- logical cure rates were ≥78% with doripenem or ically evaluable patients with E. coli infection at levofloxacin in the microbiologically evaluable and baseline, and microbiological cure rate in the clini- mMITT populations (co-primary endpoint; table cally evaluable population (patients who met the XI).[134] Doripenem was also noninferior to lev-

ofloxacin in the group of microbiologically evalu- with ‘excellent’ or ‘good’,[108-111,136] or ‘cured’ or able patients with E. coli isolated at baseline in ‘improved’[112,140] clinical responses. terms of microbiological eradication rates (84.4% vs 5.4.1 Skin and Skin Structure Infections 87.2% [between-group difference –2.8; 95% CI Doripenem 250 or 500 mg twice daily for –10.0, 4.5]). Microbiological eradication rates with 5–8 days demonstrated good efficacy in the treat- doripenem or levofloxacin were 55% and 29% in ment of a range of deep-seated skin infections in a patients with levofloxacin-resistant (MIC ≥8 mg/L) small, noncomparative, Japanese study.[112] A clin- E. coli, 83% and 63% in K. pneumoniae infection, ical response (cured or improved) was seen at day 7 and 70% and 87% in P. mirabilis infection.[134] in all 19 patients (mean age at entry of 50.5 years). Results in the clinically evaluable population at The bacteriological response rate was 85% (17 of TOC supported the co-primary efficacy outcomes the 20 pathogens isolated were eradicated).[112] At shown in table XI.[134] study entry, ten patients were diagnosed with cellu- A Japanese dose-finding trial of intravenous litis, three with erysipelas, three with lymphangitis, doripenem in patients with cUTI found that there one with lymphadenitis and two with carbuncles. was no significant difference in efficacy between The most common pathogens isolated at baseline doripenem 250 or 500 mg administered twice were S. aureus, S. pyogenes and K. oxytoca.[112] daily.[138] Overall efficacy was seen in 97.4% of patients in the doripenem 250 mg twice daily group 5.4.2 Obstetric and Gynaecological Infection and 96.9% of those in the 500 mg twice daily group In a small noncomparative study, doripenem (primary endpoint). In addition, there were no sig- showed efficacy in women with moderate or severe nificant between-group differences for secondary gynaecological infection.[108] Intravenous doripen- endpoints, including effect on pyuria or bacteriuria em 250 mg administered two or three times daily, or and bacteriological response.[138] 500 mg administered twice daily for 3–14 days Two noncomparative phase II studies demonstra- (mean of 7.2 days) achieved clinical efficacy (excel- ted the efficacy of intravenous doripenem in patients lent or good response) in 89% of women (n = 54; with cUTI.[137,139] In a study evaluating doripenem mean age of 41 years) enrolled in this study. Bacteri- 125–500 mg twice daily or 500 mg three times daily ological eradication was evident in 80% of microbi- administered for 3–15 days in patients with respira- ologically evaluable patients (24 of 30 patients).[108] tory tract infections or cUTIs, overall efficacy was Gynaecological infections included in this study seen in 94% of patients with cUTIs (n = 32), with a were parametritis (18 patients), pelvic peritonitis bacterial eradication rate of 97% (n = 34).[137] In the (14 patients), uterine adnexitis (10 patients), in- other study,[139] which included 6 patients with acute trauterine infection (9 patients) and pouch of Doug- prostatitis, 5 patients with epididymitis and 21 pa- las abscess (3 patients). Infections were severe in tients with cUTI, doripenem 250 mg two or three 41 patients and moderate in the remaining 13 pa- times daily or 500 mg twice daily for 3–14 days tients.[108] Pathogens were isolated at baseline in achieved 84% clinical efficacy judged by attending 33 patients, and these included S. aureus, Group B urologists (27 of 32 patients), and bacterial eradica- Streptococcus, E. faecium, E. coli, P. aeruginosa tion was 97% (33 of 34 strains isolated at baseline). and various anaerobes. Two-thirds of patients who When assessed by Japanese UTI committee criteria, were microbiologically evaluable (21 of 30 patients) overall clinical efficacy for cUTIs (n = 16) was had polymicrobial infection.[108] [139] 100%. 5.4.3 Sepsis and Endocarditis Intravenous doripenem 500 mg two or three 5.4 Other Infections times daily administered for 3–14 days in patients Several small, noncomparative studies in Japa- with sepsis (n = 9) and for 28 days in patients with nese patients have examined the efficacy of intrave- infective endocarditis (n = 2) was associated with nous doripenem in a variety of moderate or serious clinical cure and eradication of bacterial pathogens bacterial infections.[108-112,136,140] In these studies, in all patients in a small study.[140] Patients were clinical efficacy refers to percentages of patients aged 59–79 years and had APACHE II scores rang-

ing from 6 to 16.[140] Sepsis was secondary to uro- In 15 patients with ophthalmic infection (eight pa- logical infection in seven patients and surgery in two tients had pathogens isolated at baseline), intrave- patients and, where identified, causative pathogens nous doripenem achieved a clinical response in were E. coli and K. pneumoniae.[140] The causative 100% of patients and bacteriological eradication of organisms in patients with infective endocarditis all causative pathogens.[111] Doripenem 250 mg two were Streptococcus spp. (S. sanguis and S. vestibu- or three times daily, or 500 mg twice daily was laris [MICs not reported]).[140] administered for 5–12 days (no local treatment was administered). Ten patients were diagnosed with 5.4.4 Ear, Nose and Throat Infections corneal ulcer; four patients had an orbital infection In 12 adult patients with moderate to severe otitis and one patient had endophthalmitis.[111] The most media or tonsillitis (including peritonsillar abscess), common organisms isolated at baseline were intravenous doripenem achieved clinical efficacy in Corynebacterium spp. (two corneal ulcer and one 92% of patients (11 of 12 patients) and a bacterio- endophthalmitis patients) and P. aeruginosa (two logical eradication rate of 92% (11 of 12 organ- corneal ulcer patients).[111] isms).[109] Patients were aged 23–70 years and 8 of 12 patients were described as having severe, rather than moderate, infection. Doripenem 250 mg two or 6. Tolerability three times daily, or 500 mg twice daily was administered for 6–7 days. The most common pathogens Discussion in this section is based on data from isolated at baseline were S. aureus, S. pyogenes and the seven randomized, multicentre, comparative P. aeruginosa.[109] clinical studies[126,127,129,131-135] reviewed in section In a study of doripenem 250 mg two or three 5, supplemented by data from the Japanese[12] and times daily, or 500 mg twice daily for 3–14 days in the US[13] prescribing information. patients with a range of serious infections (n = 105), Doripenem was generally well tolerated in both clinical efficacy was achieved at treatment end in Japanese and non-Japanese patients in clinical both of the patients who had peritonsillar ab- trials,[12,13] and adverse events were mild or moder- scess.[136] ate in severity.[126,127,129,131,132,134,135] In individual trials, treatment-emergent adverse events (regard- 5.4.5 Dental and Oral Surgical Infection less of causality) were reported in 35–83% of Intravenous doripenem showed efficacy in a doripenem recipients,[127,131,132,134] 27–78%[127,131,132] small study in 24 patients with osteitis or cellulitis [110] of meropenem recipients and 60% of levofloxacin associated with dental or oral infection. Clinical recipients.[134] In two trials in patients with efficacy at end of treatment was achieved in 100% cIAIs[131,132] and a trial in patients with cUTIs in- of patients and bacteriological eradication was evi- [134] [110] cluding pyelonephritis, the most common ad- dent in 96% of patients (23 of 24 patients). verse events occurring in ≥1% of patients who re- Doripenem 250 mg two or three times daily, or ceived doripenem, meropenem or levofloxacin, re- 500 mg twice daily was administered for 3–7 days. gardless of causality, were headache, nausea, Most infections were polymicrobial, and included a diarrhoea, anaemia, phlebitis and rash (figure 3).[13] mixture of aerobic Gram-positive or Gram-negative Treatment-related adverse events were uncom- bacteria and anaerobes. The most common patho- mon (incidence of 4.4%; 37 of 835 patients) in gens isolated at baseline were Streptococcus spp. Japanese doripenem recipients (835 individuals (S. sanguis, S. mitis, S. oralis and S. constel- evaluable at the time of approval in Japan),[12] and latus).[110] diarrhoea (0.7%) and rash (0.6%) were the most 5.4.6 Ophthalmic Infection frequent adverse events reported. The incidence Doripenem penetrates aqueous humor, evidenced of treatment-related adverse events with doripenem by concentrations of the drug of 0.16–0.87 mg/L or comparator drugs did not differ significantly within 1–2 hours of starting an infusion of a 250 mg in the individual randomized, comparative intravenous dose.[111] Consequently, doripenem has trials,[126,127,129,133-135] and the most frequent treat- been studied in patients with ophthalmic infection. ment-related adverse events in any treatment arm

were gastrointestinal (mainly nausea or diarrhoea), three trials and few patients discontinued doripenem headache and phlebitis. therapy because of an adverse event (0.2% due to nausea, 0.1% due to vulvomycotic infection and Severe treatment-related adverse events, such as 0.1% due to rash).[13] No treatment-related serious hypersensitivity reactions or Clostridium difficile adverse events were reported in the individual ran- colitis, were rare (both at frequency of <1%) in these domized trials.[127,131,132,134,135] a Laboratory abnormalities were generally infre- quent in clinical trials in non-Japanese patients with 20 DOR cIAI, cUTI or nosocomial pneumonia.[129,131,132,134] 18 MEM For example, in the cIAI and cUTI trials, elevated 16 liver enzymes occurred in 1–2% of doripenem recip- 14 ients, 3% of ciprofloxacin recipients and 3% of 12 meropenem recipients.[13] Abnormal laboratory re- 10 sults were reported in 23.8% of Japanese individuals 8 (818 evaluable) who had received doripenem up to 6 Incidence (% of pts) the time of approval of the drug in Japan.[12] The 4 most frequent abnormalities were increased ALT 2 [12] 0 (12.7%) or AST (9.7%) levels. In the randomized comparisons between doripenem and meropenem in Rash Japanese patients, the incidence and type of treat- Nausea Anaemia Phlebitis Headache Diarrhoea ment-related abnormal laboratory results did not differ between the doripenem and meropenem b groups.[127,135] 20 DOR Seizures were reported in 0–1.3% of doripenem, 18 LVX 0% of meropenem, 0.3% of levofloxacin, 2.7% 16 of piperacillin/tazobactam and 3.8% of imipenem/ 14 cilastin recipients in the randomized, comparative 12 trials;[126,127,129,131,132,134,135] however, apart from one 10 incident in an imipenem/cilastin recipient,[129] all 8 were thought to be unrelated to the study medica- 6 tion.[126,129,134] Few patients died in any of these Incidence (% of pts) 4 clinical trials, and none of the deaths reported 2 were deemed related to the study med- 0 ication.[126,127,129,131,132,134,135]

Rash Treatment-emergent anaphylaxis, interstitial Nausea Anaemia Phlebitis Headache Diarrhoea pneumonia, Stevens Johnson syndrome, seizure and Fig. 3. Tolerability of intravenous doripenem (DOR) in adult pa- toxic epidermal necrolysis have been observed with tients (pts) with complicated urinary tract infections (cUTIs) or com- doripenem therapy during postmarketing surveil- plicated intra-abdominal infections (cIAIs). (a) Combined results[13] lance, although frequency and causality have not [131,132] of two trials in which patients with cIAIs received 5–14 days [13] of intravenous DOR 500 mg every 8 hours infused over 60 min been established. Doripenem is currently contra- (n = 477) or meropenem (MEM) 1 g every 8 hours administered as indicated in patients who have demonstrated ana- a bolus over 3–5 min (n = 469) and (b) results[13] of a trial[134] in phylactic reactions to β-lactam agents or who have a which patients with cUTIs were treated for a total of 10 days with known sensitivity to carbapenems.[12,13] intravenous DOR 500 mg every 8 hours (n = 376) or levofloxacin (LVX) 250 mg once daily (n = 372), each administered as a 60-min infusion, with the option after 3 days (after at least nine doses of 7. Dosage and Administration DOR or at least three doses of LVX) of switching to oral LVX 250 mg once daily for the remainder of the treatment period. Ad- verse events occurring in ≥1% of patients in any treatment arm, Doripenem is indicated in Japan for use as a regardless of cause. single agent in the treatment of adult patients with a

wide range of infections (see table XII) caused by containing 500 mg in 10 mL then diluted with susceptible strains of Staphylococcus spp., Strepto- 100 mL of sodium chloride 0.9% or dextrose 5% in coccus spp., Enterococcus spp. (except E. faecium), the US and EU.[13,14] At a controlled room tempera- M. catarrhalis, E. coli, Citrobacter spp., Klebsiella ture, doripenem solution is stable for up to 4 hours spp., Enterobacter spp., Serratia spp., Proteus spp., when reconstituted with dextrose and up to 12 hours M. morganii, Providencia spp., H. influenzae, when reconstituted with physiological saline. At a P. aeruginosa, Acinetobacter spp., Peptostreptococ- refrigerated temperature of 2–8°C protected from cus spp., Bacteroides spp. and Prevotella spp.[12] light, the drug is stable for up to 24 hours in a The recommended dosage regimen in Japan is dextrose solution and up to 72 hours in physiologi- 250 mg two or three times daily (infused over cal saline.[14] 30–60 minutes), although the dosage can be in- Dosage adjustment is recommended for patients creased, depending on patient age and symptoms.[12] with renal impairment.[12-14] Doripenem is not re- The maximum individual dose is 500 mg, and the commended in patients aged <18 years because of a maximum daily dosage is 1.5 g/day.[12] lack of efficacy and tolerability data.[12-14] In the US, doripenem is indicated as a single The local manufacturer’s prescribing information agent for the treatment of adult patients (aged should be consulted for other contraindications, ≥18 years) with cIAIs or cUTIs, including pyelone- drug interactions, monitoring requirements, precau- phritis, caused by susceptible strains of designated tions, details of dosage adjustments in renal impair- pathogens.[13] For cIAIs, these pathogens are B. cac- ment and use in other special patient populations. cae, B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, E. coli, K. pneumoniae, P. micros, 8. Place of Doripenem in the P. aeruginosa, S. constellatus and S. intermedius; Management of Bacterial Infections for cUTIs, including pyelonephritis, they are Prompt and appropriate use of antimicrobial ther- A. baumannii, E. coli (including patients with con- apy, including using local microbiological data in current bacteraemia), K. pneumoniae, P. mirabilis selecting appropriate treatment,[143-145] is important [13] and P. aeruginosa. in reducing morbidity and mortality associated with The recommended dosage regimen for doripen- serious bacterial infections.[2,144,146] em in the US is 500 mg every 8 hours (infused over Among the antibacterial agents commonly used 60 minutes) for 5–14 days (patients with cIAIs) or in this setting are the carbapenems, a class of broad- 10 days (patients with cUTIs, including pyelone- [13] phritis). In patients with cUTIs, including pyelo- Table XII. Approved indications for intravenous doripenem in Ja- nephritis, and concurrent bacteraemia, doripenem pan[12] [13] can be administered for up to 14 days. Patients Sepsis, infective endocarditis may be switched to an orally administered antibac- Deep-seated skin infections, lymphangitis/lymphadenitis terial agent after 3 days of doripenem therapy upon Secondary infection from trauma, burns, surgical wounds, etc. the demonstration of clinical improvement.[13] Osteomyelitis, arthritis Doripenem is approved in the EU for use in adult Pharyngitis/laryngitis, tonsillitis (including peritonsillitis and patients with nosocomial pneumonia (including peritonsillar abscesses VAP), cIAIs and cUTIs.[14] The recommended dos- Pneumonia, pulmonary abscess, empyema, secondary infections due to chronic respiratory lesions age in the EU is 500 mg every 8 hours, for Complicated cystitis, pyelonephritis, acute or chronic prostatitis, 5–14 days, infused over 1 hour in patients with epididymitis cIAIs or cUTIs (including pyelonephritis) and over Peritonitis, intraperitoneal abscess 1 or 4 hours in patients with nosocomial pneumonia Cholecystitis, cholangitis, hepatic abscess [14] (including VAP). Intrauterine infection, uterine adnexitis, parametritis Doripenem is formulated as a powder for recon- Orbital infection, keratitis (including corneal ulcers), stitution with 100 mL of physiological saline (sodi- endophthalmitis (including panophthalmitis) um chloride 0.9%) in Japan,[12] or with sterile water Otitis media or sodium chloride 0.9% to produce a suspension Perimandibular phlegmon, jaw inflammation

spectrum β-lactam antibacterials identified in the over 30–60 minutes,[12,13] although more aggressive 1970s.[1] In addition, panipenem/betamipron[11] (ap- administration scheduled may be required in criti- proved in Japan, China and Korea) and biapenem[10] cally ill patients with altered pharmacokinetics (e.g. (approved in Japan) have been available for several with increased Vd).[144] In contrast, ertapenem is not years.[1] Doripenem was approved in Japan in 2005 suited for empirical use in nosocomial infections for use in a wide range of serious infections due to because of an absence of activity against non-fer- Gram-negative, Gram-positive or anaerobic patho- mentative Gram-negative pathogens.[8] Doripenem gens,[12] in the US in late 2007 for use in adult (like meropenem,[5-7,150] ertapenem[8,9] or biape- patients with cIAIs or cUTIs,[13] and in the EU in nem,[10] but unlike imipenem[4] or panipenem[11]) is 2008 in adult patients with nosocomial pneumonia stable to the human renal enzyme DHP-1 (section (including VAP), cIAIs and cUTIs.[14] Doripenem is 2.1) and does not need to be coadministered with a currently undergoing pre-approval review for use DHP-1 inhibitor to achieve clinical efficacy (e.g. in nosocomial pneumonia, including VAP, in the cilastin plus imipenem[4]) or to reduce nephrotoxic US[147] and for use in adult patients with cIAIs, potential (e.g. betamipron plus panipenem[11]). cUTIs or nosocomial pneumonia, including VAP, in Doripenem is also resistant to inactivation by most other countries worldwide.[147] β-lactamases, including ESBLs (section 2). [150] [4] Imipenem/cilastin or meropenem are well estab- Like meropenem or imipenem, doripenem 1 β lished, appropriate choices for the empirical treat- has a short t /2 (section 3); consequently, doripenem ment of serious bacterial infections in a hospital requires administration two or three times daily, setting, including nosocomial infections, because of usually as a 30- to 60-minute infusion (section 7). [144] their broad spectrum of antibacterial activity and Unlike the other available carbapenems, good efficacy.[1,144] Meropenem is administered eve- doripenem is stable at room temperature for up to ry 8 hours as a 500 mg dose infused over 15–30 12 hours when reconstituted with normal saline minutes (skin and skin structure infections), or a (section 7), which means that it may have potential 1000 mg dose administered as a 15- to 30-minute for prolonged infusion regimens (e.g. the 4-hour [129] infusion or as an intravenous bolus injection (in infusion used in a clinical trial in VAP [section cIAIs),[148] while imipenem/cilastin is usually ad- 5.1.1]), thus achieving the T > MICfree targets re- ministered every 6 or 8 hours as a 500 mg dose quired in more difficult-to-treat nosocomial infec- [143] infused over 40–60 minutes (in moderate or severe tions. infections with susceptible organisms).[149] In gener- Plasma concentrations of doripenem are estimat- al, imipenem has slightly greater activity against ed to achieve an optimal bactericidal pharmacody- Gram-positive organisms than meropenem, while namic target attainment against most pathogens meropenem is slightly more active than imipenem associated with serious bacterial infections, includ- against Gram-negative organisms.[1] Nevertheless, ing nosocomial pneumonia, cUTI or cIAI (section both have broad-spectrum activity, including 4). The drug has shown good penetration into a wide against non-fermenting Gram-negative bacteria. range of tissues, including lung, intra-abdominal, Doripenem, although more recently approved, is and head and neck tissues, and peritoneal fluid, and considered a viable alternative to these agents be- demonstrates low serum protein binding (section 3). cause of its similar spectrum of activity and clinical Doripenem demonstrated in vitro activity against efficacy to imipenem against Gram-positive organ- a wide range of Gram-negative, Gram-positive and isms and to meropenem against Gram-negative or- anaerobic organisms associated with serious or ganisms,[144] and good activity against P. aeruginosa nosocomially acquired infections (section 2.2), and and other non-fermentative Gram-negative bacil- has rapid, time-dependent bactericidal activity li.[1,68] Importantly, doripenem activity against against clinically important Gram-negative and Gram-negative pathogens is generally 2- to 4-fold Gram-positive pathogens (including P. aeruginosa, greater than that of imipenem (section 2.2.1).[144] E. coli and S. aureus) and various anaerobes. In Doripenem is usually administered every 8 hours as addition, doripenem has an in vitro PAE of ≈2 hours a 250 mg (in Japan only) or 500 mg dose infused against P. aeruginosa and S. aureus (section 2.2.5).

This broad spectrum of activity means that doripen- guidelines were published prior to the approval of em is suitable for use as an empirical treatment for doripenem outside of Japan, and thus do not include serious bacterial infections, such as serious lower doripenem among the carbapenems recommended. respiratory infections (including nosocomial pneu- Japanese guidelines[158,159] support the use of monia, VAP or severe CAP), cIAI, cUTIs, gynaeco- doripenem, meropenem or imipenem/cilastin as a logical and obstetric infections and sepsis, especial- second-line option in the treatment of moderate or ly as these conditions are often polymicrobial, in- severe cholangitis[158] and use of carbapenems in cluding mixed aerobic/anaerobic, infections. Like severe pneumococcal pneumonia requiring inpatient meropenem[150] or biapenem,[10] doripenem had a treatment or as empirical therapy in combination low propensity for inducing seizures in animal stud- with new quinolones, tetracyclines or macrolides in ies (section 2.5) and was not associated with patients with severe CAP who require admission to seizures in clinical trials (section 6).[44] However, the intensive care unit.[159] further investigation in a clinical setting is required Increased and/or inappropriate use of broad- to confirm these results. spectrum antibacterial agents, such as the third- Numerous randomized, phase III clinical trials generation cephalosporins, in serious bacterial in- have shown doripenem to be an effective and well fections has resulted in a global increase in resistant tolerated treatment in a wide range of serious bacter- bacterial strains, including ESBL- and AmpC-pro- ial infections (section 5). Doripenem was as effec- ducing Enterobacteriaceae, and multidrug-resistant tive as comparator antibacterials, including P. aeruginosa.[2,146,160] Because of their broad spec- meropenem in complicated lower respiratory infec- trum of activity, carbapenems are considered first- tions, cIAIs and cUTIs, imipenem/cilastin or piper- line options in the empirical treatment of serious acillin/tazobactam in nosocomial pneumonia (in- infections that may be associated with ESBL-pro- cluding VAP) and levofloxacin in cUTIs (section ducing Enterobacteriaceae or P. aeruginosa.[160] Im- 5.1, section 5.2 and section 5.3). Doripenem also portantly, doripenem retains activity against ESBL- demonstrated efficacy in a range of other infections, and AmpC-producing Enterobacteriaceae, with little including cSSSI, obstetric or gynaecological infec- or no increase in MIC90 values when compared with tions, sepsis and endocarditis, severe ENT, dental or wild-type isolates, has no inoculum effect (section oral surgical infections and severe ophthalmic infec- 2.2 and section 2.3) and a low propensity to select tions (section 5.4). for resistance (section 2.3). Pharmacoeconomic analyses of doripenem, in- Antimicrobial resistance to the non-fermentative cluding analyses based on efficacy and hospital re- Gram-negative pathogens Acinetobacter spp. and source utilization data discussed in section 5, would P. aeruginosa is increasing worldwide, and mul- be useful in determining the cost effectiveness of the tidrug-resistant isolates of P. aeruginosa and drug, relative to other carbapenems or conventional A. baumanii are often associated with nosocomial combination antibacterial treatments in patients with infection.[161-164] Doripenem showed in vitro activity serious bacterial infections. against ceftazidime- or imipenem-susceptible, or International treatment guidelines[151-157] support non-multidrug-resistant P. aeruginosa isolates in all the use of carbapenems, such as imipenem/cilastin geographic regions, evidenced by MIC90 values of or meropenem, as an option in the initial treatment 0.2–12.5 mg/L and, in some studies, susceptibility of nosocomial pneumonia and/or severe CAP (in rates of 100% (section 2.2). Nevertheless, like other combination with ciprofloxacin where there is a risk carbapenems, doripenem activity against resistant of P. aeruginosa),[153-155] cUTIs,[156] incisional sur- P. aeruginosa isolates was more limited, with sus- gical site infection after intestinal or genital tract ceptibility rates of ≤40% and MIC90 values of surgery,[151] and severe IAIs,[152] and list carbape- 8–64 mg/L (section 2.2). Doripenem activity against nems in a range of first-line regimens in the treat- A. baumanii (including ceftazidime intermediate/ ment of polymicrobial necrotizing infections of the resistant isolates) was limited in Europe and the skin, fascia and muscle, or as intravenous options in Americas, with a susceptibility rate of 76–78% and infections after a human or an animal bite.[151] These MIC90 values of 1–32 mg/L; however, lower MIC90

values for Acinetobacter spp. were reported in Japan once reconstituted), doripenem solution is stable for (0.78–3.13 mg/L) [section 2.2]. As a consequence of up to 12 hours at a controlled room temperature its broad spectrum of in vitro activity against Gram- when reconstituted with physiological saline (sec- negative bacteria, including those pathogens resis- tion 7). Consequently, doripenem is suitable for tant to other antibacterials, doripenem has potential prolonged infusion regimens, such as the 4-hour as a new option in the empirical treatment of patients infusion used in a trial in patients with VAP[129] with severe nosocomial infections, including in set- (section 5.1.1). tings where there are increased rates of multidrug- In conclusion, doripenem has a broad spectrum resistant Gram-negative bacteria.[144,165] of in vitro activity against Gram-positive and Gram- Of interest, penicillin- or macrolide-resistant negative pathogens, including ESBL- and AmpC- S. pneumoniae isolates are more common in Asia producing Enterobacteriaceae, and anaerobic bacte- (including Japan) than in Western countries. [166] In ria. The drug also has a low propensity to select for Japan, >50% of macrolide-resistant isolates are erm resistance and is suitable for the prolonged infusions B-positive, which is usually associated with higher that may be required to achieve pharmacodynamic/ MICs than mef A-positive isolates.[159] Doripenem pharmacokinetic targets for bactericidal activity showed good in vitro activity against S. pneu- (and therefore efficacy) against pathogens with in- moniae, including ceftriaxone-resistant, penicillin- creased MICs. Doripenem is at least as effective as intermediate or -resistant or multidrug-resistant iso- other antibacterial agents, including meropenem, lates (sections 2.2 and 2.3). imipenem/cilastin, piperacillin/tazobactam or lev- Methicillin or oxacillin-resistant S. aureus, ofloxacin, in the treatment of a variety of serious E. faecium and S. maltophilia (section 2.2) are inher- bacterial infections (e.g. complicated lower respira- ently resistant to doripenem and other currently tory infections, nosocomial pneumonia [including available carbapenems.[1] Although the preva- VAP], cIAIs and cUTIs), and is well tolerated. Thus, lence of acquired metallo-β-lactamases and doripenem is a valuable addition to the options carbapenemases is increasing (section 2.3),[78,88] available for the empirical treatment of hospitalized carbapenem resistance remains uncommon and En- patients with serious bacterial infections. terobacteriaceae resistance to carbapenems is rare (section 2.3).[47,160] However, it is important that Disclosure doripenem (and other carbapenems) are used appro- The preparation of this review was not supported by any priately as empirical treatment to limit the likelihood external funding. During the peer review process, the manu- [2] of increasing future resistance. Ideally, doripenem facturer of the agent under review was offered an opportunity should only be used in a hospital setting in severe to comment on this article. Changes resulting from comments infections for the shortest possible duration. received were made on the basis of scientific and editorial As mentioned in section 4, the pharmacodynam- merit. ic/pharmacokinetic parameter that best correlates with carbapenem bactericidal activity (and therefore References 1. Zhanel GG, Wiebe R, Dilay L, et al. Comparative review of the efficacy) is T > MICfree, and a T > MICfree of carbapenems. Drugs 2007; 67 (7): 1027-52 30–40% is adequate for carbapenem efficacy. Of 2. Kollef M. Appropriate empirical antibacterial therapy for interest, in animal model of infections, increasing nosocomial infections: getting it right the first time. Drugs 2003; 63 (20): 2157-68 the doripenem dose administration frequency or 3. Shimada J, Yamaguchi K, Shiba T, et al. A new carbapenem lengthening the infusion duration was associated antibiotic for injection: characteristics of doripenem [in Japa- nese]. Jpn J Antibiot 2005 Dec; 58 (6): 489-506 with a prolonged T > MICfree and enhanced bacteri- 4. Balfour JA, Bryson HM, Brogden RN. Imipenem/cilastin: an cidal activity, compared with increasing the dose per update of its antibacterial activity, pharmacokinetics and thera- administration (section 4). This is particularly im- peutic efficacy in the treatment of serious infections. Drugs 1996 Jan; 51 (1): 99-136 portant when considering pathogens with increased 5. Lowe MN, Lamb HM. Meropenem: an updated review of its use MICs, including P. aeruginosa. Unlike mer- in the management of intra-abdominal infections. Drugs 2000 [148] [149] Sep; 60 (3): 619-46 openem or imipenem (which maintain poten- 6. Hurst M, Lamb HM. Meropenem: a review of its use in patients cy for only 2[148] or 4[149] hours at room temperature in intensive care. Drugs 2000 Mar; 59 (3): 653-80

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Brown NP, Jones ME, Draghi DC, et al. Baseline surveillance 2008 Apr; 52 (4): 1510-2 profile of doripenem against key Gram-negative pathogens 16. Fujimura T, Kimura Y, Yoshida I, et al. In vitro antibacterial encountered in the United States [abstract no. E221 plus post- activity of doripenem, a novel parenteral carbapenem [in Japa- er]. 46th Interscience Conference on Antimicrobial Agents and nese]. Jpn J Chemother 2005; 53 Suppl. 1: 57-70 Chemotherapy; 2006 Sep 27-30; San Francisco (CA), 177 17. Davies TA, Bush K, Flamm RK. Differences in Escherichia coli 30. Brown NP, Jones ME, Draghi DC, et al. Profile of doripenem and Pseudomonas aeruginosa cell morphology after exposure activity against Gram-positive pathogens: results of a 2005- to doripenem, imipenem, and meropenem [abstract no. A- 2006 surveillance initiative [abstract no. E220 plus poster]. 025]. 107th General Meeting of the American Society for 46th Interscience Conference on Antimicrobial Agents and Microbiology; 2007 May 21-25; Toronto (ON) Chemotherapy; 2006 Sep 27-30; San Francisco (CA), 176-7 18. Mori M, Hikida M, Nishihara T, et al. Comparative stability of 31. Pillar CM, Aranza MK, Shah D, et al. Analysis of doripenem carbapenem and penem antibiotics to human recombinant activity, relative to other carbapenems, against target Gram- dehydropeptidase-I [letter]. J Antimicrob Chemother 1996 negative pathogens isolated from specific infection sites [ab- May; 37 (5): 1034-6 stract no. E-262 plus poster]. 47th Annual Interscience Confer- 19. Yamano Y, Kawai Y, Yutsudo T. Stability of doripenem against ence on Antimicrobial Agents and Chemotherapy; 2007 Sep human renal dehydropeptidase-I [in Japanese]. Jpn 17-20; Chicago (IL), 185 J Chemother 2005; 53 Suppl. 1: 92-5 32. Fritsche TR, Stilwell MG, Jones RN. Antimicrobial activity of 20. Turnidge JD, Bell JM, Fritsche TR, et al. Doripenem activity doripenem (S-4661): a global surveillance report (2003). Clin tested against Gram-negative pathogens in the Asia-Pacific Microbiol Infect 2005 Dec; 11 (12): 974-84 (APAC) region: report from the SENTRY Antimicrobial Sur- 33. Kaniga K, Prokimer P, Llorens L, et al. Prevalence of extended- veillance Program, 2006 [abstract no. E260 plus poster]. 47th spectrum beta-lactamase (ESBL) and fluoroquinolone-resis- Annual Interscience Conference on Antimicrobial Agents and tant isolates from phase 3 trials of nosocomial pneumonia and Chemotherapy; 2007 Sep 17-20; Chicago (IL) their susceptibility to doripenem (DOR) [abstract no. E265]. 21. Evangelista AT, Yee YC, Pillar CM, et al. Surveillance profiling 47th Annual Interscience Conference on Antimicrobial Agents of doripenem (DOR) activity against Pseudomonas aerugi- and Chemotherapy; 2007 Sep 17-20; Chicago (IL) nosa (PA) isolated from inpatients (IP) and ICU patients 34. Queenan AM, Shang W, Amsler K, et al. Characterization of (ICU); results of the TRUST surveillance initiative [abstract ESBLs from Enterobacteriaceae collected during doripenem no. 523]. 45th Annual Infectious Diseases Society of America; clinical trials [abstract no. C2-1519]. 47th Annual Interscience 2007 Oct 4-7; San Diego (CA), 159 Conference on Antimicrobial Agents and Chemotherapy; 2007 22. Fritsche TR, Sader HS, Strabala P, et al. Antimicrobial activities Sep 17-20; Chicago (IL) of doripenem and other carbapenems tested against Pseudo- 35. Kaniga K, Umeh O, Llorens L, et al. Activity of doripenem monas aeruginosa, other non-fermentative bacilli and Aer- against isolates from phase 3 trials of complicated intra-abdo- omonas spp [abstract no. E-0222 plus poster]. 46th Inter- minal infections [abstract no. E-264 plus poster]. 47th Annual science Conference on Antimicrobial Agents and Chemother- Interscience Conference on Antimicrobial Agents and Chemo- apy; 2006 Sep 27-30; San Francisco (CA), 177 therapy; 2007 Sep 17-20; Chicago (IL) 23. Fritsche TR, Sader HS, Strabala P, et al. Activity of doripenem 36. Kaniga K, Redman R, Llorens L, et al. Prevalence of extended- tested against an international collection of ESBL- and AmpC- spectrum beta-lactamase producers (ESBLs) and fluoroquino- producing Enterobacteriaceae [abstract no. E-0219 plus post- lone-resistant isolates from phase 3 trials of complicated urin- er]. 46th Interscience Conference on Antimicrobial Agents and ary tract infections (UTIs) including pyelonephritis [abstract Chemotherapy; 2006 Sep 27-30; San Francisco (CA), 176 no. E-925 plus poster]. 47th Interscience Conference on Anti- 24. Fritsche T, Sader HS, Strabala P, et al. Spectrum and activity of microbial Agents and Chemotherapy; 2007 Sep 17-20; Chica- doripenem, an investigational carbapenem, tested against bac- go (IL)

37. Goldstein EJ, Citron DM, Merriam CV, et al. In vitro activities 52. Yamano Y, Nishikawa T, Fujimura T, et al. Occurrence of PER- of doripenem and six comparator drugs against 423 aerobic 1 producing clinical isolates of Pseudomonas aeruginosa in and anaerobic bacterial isolates from infected diabetic foot Japan and their susceptibility to doripenem. J Antibiot (Tokyo) wounds. Antimicrob Agents Chemother 2008 Feb; 52 (2): 761- 2006 Dec; 59 (12): 791-6 6 53. Nomura S, Nagayama A. In vitro antibacterial activity of S- 38. Aranza MK, Pillar CM, Shah D, et al. Stratified analysis of 4661, a new parenteral carbapenem, against urological patho- doripenem activity against Enterobacteriaceae and Pseudo- gens isolated from patients with complicated urinary tract monas aeruginosa according to patient location: inpatients and infections. J Chemother 2002 Apr; 14 (2): 155-60 ICU patients [abstract no. E-263 plus poster]. 47th Interscience 54. Mikamo H, Izumi K, Hua YX, et al. In vitro and in vivo Conference on Antimicrobial Agents and Chemotherapy; 2007 antibacterial activities of a new injectable carbapenem, S- Sep 17-20; Chicago (IL) 4661, against gynaecological pathogens. J Antimicrob 39. Brown SD, Traczewski MM. Comparative in vitro antimicrobial Chemother 2000 Sep; 46 (3): 471-4 activity of a new carbapenem, doripenem: tentative disc diffu- 55. Watanabe A, Takahashi H, Kikuchi T, et al. Comparative in sion criteria and quality control. J Antimicrob Chemother 2005 vitro activity of S-4661, a new parenteral carbapenem, and Jun; 55 (6): 944-9 other antimicrobial agents against respiratory pathogens. 40. Fritsche TR, Johnson D, Jones RN. Antimicrobial activity of Chemotherapy 2000 May 30; 46 (3): 184-7 doripenem against multi-drug resistant Pseudomonas aerugi- 56. Shimauchi C, Kaneko K, Sato Y, et al. Comparative basic study nosa and Streptococcus pneumoniae [abstract no. E2014]. 44th of carbapenems antibiotics against Pseudomonas aeruginosa Interscience Conference on Antimicrobial Agents and Chemo- [in Japanese]. Jpn J Chemother 2005; 53 (12): 732-40 therapy; 2004 Oct 30-Nov 2; Washington DC, 175 57. Kuwahara-Arai K, Hiramatsu K. In vitro activity of doripenem 41. Ge Y, Wikler MA, Sahm DF, et al. In vitro antimicrobial against Gram-positive and Gram-negative bacteria isolates [in activity of doripenem, a new carbapenem. Antimicrob Agents Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 17-23 Chemother 2004 Apr; 48 (4): 1384-96 58. Miwa H, Kimura Y, Jinushi Y, et al. Antipseudomonal activity 42. Hecht DW, Galang MA, Sambol SP, et al. In vitro activities of of doripenem, a novel parenteral carbapenem antibiotic [in 15 antimicrobial agents against 110 toxigenic Clostridium Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 80-91 difficile clinical isolates collected from 1983 to 2004. An- 59. Okamoto R, Nakano R, Sato Y, et al. Antibacterial activity of β timicrob Agents Chemother 2007 Aug; 51 (8): 2716-9 doripenem against -lactamase-producing strains [in Japa- nese]. Jpn J Chemother 2005; 53 Suppl. 1: 47-51 43. Credito KL, Ednie LM, Appelbaum PC. Comparative antianaer- β obic activities of doripenem determined by MIC and time-kill 60. Tanaka K, Watanabe K. In vitro activity of doripenem, a 1 - analysis. Antimicrob Agents Chemother 2008 Jan; 52 (1): 365- methylcarbapenem, against anaerobic bacteria [in Japanese]. 73 Jpn J Chemother 2005; 53 Suppl. 1: 24-31 61. Yoshida I, Sugimori G, Higashiyama I, et al. Surveillance of 44. Jones RN, Huynh HK, Biedenbach DJ. Activities of doripenem susceptibility of clinical isolates of various bacterial species to (S-4661) against drug-resistant clinical pathogens. Antimicrob antibacterial agents: antimicrobial activity against Gram-nega- Agents Chemother 2004 Aug; 48 (8): 3136-40 tive bacteria isolated in 2000 [in Japanese]. Jpn J Chemother 45. Jones RN, Huynh HK, Biedenbach DJ, et al. Doripenem (S- 2003; 51 (4): 209-32 4661), a novel carbapenem: comparative activity against con- 62. Masuda N, Sakagawa E, Ohya S, et al. Hypersusceptibility of temporary pathogens including bactericidal action and prelim- the Pseudomonas aeruginosa nfxB mutant to β-lactams due to inary in vitro methods evaluations. J Antimicrob Chemother reduced expression of the AmpC β-lactamase. Antimicrob 2004 Jul; 54 (1): 144-54 Agents Chemother 2001 Apr; 45 (4): 1284-6 46. Mushtaq S, Ge Y, Livermore DM. Doripenem versus Pseudo- 63. Tsuji M, Furuya N, Matsumoto T, et al. In vitro and in vivo monas aeruginosa in vitro: activity against characterized iso- antibacterial activity of DRPM, a new carbapenem [in Japa- lates, mutants, and transconjugants and resistance selection nese]. Jpn J Chemother 2005; 53 Suppl. 1: 1-16 potential. Antimicrob Agents Chemother 2004 Aug; 48 (8): 64. Mikamo H, Tamaya T. Antimicrobial susceptibility and 3086-92 pharmacokinetics of doripenem in the field of obstetrics and 47. Mushtaq S, Ge Y, Livermore DM. Comparative activities of gynecology [in Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: doripenem versus isolates, mutants, and transconjugants of 286-92 Enterobacteriaceae and Acinetobacter spp. with characterized β 65. Sugihara K, Tateda K, Shibuya R, et al. In vitro activity of CS- -lactamases. Antimicrob Agents Chemother 2004 Apr; 48 023 (RO4908463) against recent clinical isolates of Gram- (4): 1313-9 positive and -negative pathogens in Japan [abstract no. E271]. 48. Traczewski MM, Brown SD. In vitro activity of doripenem 47th Interscience Conference on Antimicrobial Agents and against Pseudomonas aeruginosa and Burkholderia cepacia Chemotherapy; 2007 Sep 17-20; Chicago (IL) isolates from both cystic fibrosis and non-cystic fibrosis pa- 66. Kobayashi Y, Sumitani Y, Sugita K, et al. Antimicrobial activity tients. Antimicrob Agents Chemother 2006 Feb; 50 (2): 819- of meropenem against main bacterial species isolated from 21 patient blood in 2006 [in Japanese]. Jpn J Antibiot 2007 Dec; 49. Wexler HM, Engel AE, Glass D, et al. In vitro activities of 60 (6): 378-86 doripenem and comparator agents against 364 anaerobic clin- 67. Chen Y, Garber E, Zhao Q, et al. In vitro activity of doripenem ical isolates. Antimicrob Agents Chemother 2005 Oct; 49 (10): (S-4661) against multidrug-resistant Gram-negative bacilli 4413-7 isolated from patients with cystic fibrosis. Antimicrob Agents 50. Davies TA, Shang W, Bush K, et al. Activity of doripenem and Chemother 2005 Jun; 49 (6): 2510-1 comparator β-lactams against US clinical isolates of Strepto- 68. Jones RN, Sader HS, Fritsche TR, et al. Selection of a surrogate coccus pneumoniae with defined mutations in the penicillin- β-lactam testing agent for initial susceptibility testing of binding domains of pbp1a, pbp2b and pbp2x [letter]. J Antimi- doripenem, a new carbapenem. Diagn Microbiol Infect Dis crob Chemother 2008 Mar; 61 (3): 751-3 2007 Dec; 59 (4): 467-72 51. Jones RN, Sader HS, Fritsche TR. Comparative activity of 69. Clinical and Laboratory Standards Institute. Performance stan- doripenem and three other carbapenems tested against Gram- dards for antimicrobial susceptibility testing; eighteenth infor- negative bacilli with various β-lactamase resistance mechan- mational supplement. M100-S18 Vol.28 No 1. Wayne (PA): isms. Diagn Microbiol Infect Dis 2005 May; 52 (1): 71-4 Clinical and Laboratory Standards Institute, 2008 Jan

70. Nishino T, Otsuki M, Izawa M. In vitro and in vivo antibacterial moniae isolates. Diagn Microbiol Infect Dis 2007 Jan; 57 (1): activity of doripenem [in Japanese]. Jpn J Chemother 2005; 53 85-91 Suppl. 1: 32-46 87. Morrow BJ, Andrew T, Queenan A, et al. P. aeruginosa DNA 71. Clinical and Laboratory Standards Institute. Methods for anti- microarray analysis reveals differential induction of ampC and microbial susceptibility testing of anaerobic bacteria; approved efflux by imipenem and doripenem [abstract no. C1-0037 plus standard - seventh edition. M11-A7 Vol 27 No. 2. Wayne poster]. 46th Interscience Conference on Antimicrobial Agents (PA): Clinical and Laboratory Standards Institute, 2008 Jan and Chemotherapy; 2006 Sep 27-30; San Francisco (CA), 66 72. Mushtaq S, Warner M, Ge Y, et al. In vitro interactions of 88. Queenan AM, Shang W, Flamm RK, et al. Effect of doripenem doripenem with other antibacterials [abstract no. E-307]. 45th on AmpC induction in Enterobacteriaceae and Pseudomonas Annual Interscience Conference on Antimicrobial Agents and aeruginosa [abstract no. C1-0040 plus poster]. 46th Inter- Chemotherapy; 2005 Dec 16-19; Washington, DC science Conference on Antimicrobial Agents and Chemother- 73. Foleno B, Wira E, Bush K, et al. Ceftobiprole in-vitro interac- apy; 2006 Sep 27-30; San Francisco (CA), 66-7 tions with doripenem, levofloxacin, or colistin against Pseudo- 89. Ramsey DM, Wozniak DJ. Understanding the control of Pseu- monas aeruginosa, Acinetobacter baumannii, and fluoroquin- domonas aeruginosa alginate synthesis and the prospects for olone-resistant Escherichia coli [abstract no. 286]. 44th Annu- management of chronic infections in cystic fibrosis. Mol al Infectious Diseases Society of America; 2006 Oct 12-15; Microbiol 2005 Apr; 56 (2): 309-22 Toronto (ON), 99 90. Bagge N, Schuster M, Hentzer M, et al. Pseudomonas aerugi- 74. Kobayashi Y. Study of the synergism between carbapenems and nosa biofilms exposed to imipenem exhibit changes in global vancomycin or teicoplanin against MRSA, focusing on S- gene expression and β-lactamase and alginate production. An- 4661, a carbapenem newly developed in Japan. J Infect timicrob Agents Chemother 2004 Apr; 48 (4): 1175-87 Chemother 2005 Oct; 11 (5): 259-61 91. Andrew T, Morrow B, Bush K, et al. Pseudomonas aeruginosa 75. Ishii Y, Sugihara S, Tateda K, et al. In vitro synergistic effects of DNA microarray analysis reveals differential induction of combinations of CP3242, as a novel metallo-β-lactamase in- alginate and repression of flagellar gene expression by imipe- hibitor, and carbapenems against carbapenemase producing nem and doripenem [abstract no. A097 plus poster]. 107th organisms [abstract no. F1-331]. 47th Interscience Conference General Meeting of the American Society for Microbiology; on Antimicrobial Agents and Chemotherapy; 2007 Sep 17-20; 2007 May 21-25; Toronto (ON) Chicago (IL) 92. Huynh HK, Biedenbach DJ, Jones RN. Delayed resistance se- 76. Mushtaq S, Warner M, Kaniga K, et al. Bactericidal activity of lection for doripenem when passaging Pseudomonas aerugi- doripenem vs. Pseudomonas aeruginosa [abstract no. F-1162 nosa isolates with doripenem plus an aminoglycoside. Diagn plus oral presentation]. 45th Annual Interscience Conference Microbiol Infect Dis 2006 Jul; 55 (3): 241-3 on Antimicrobial Agents and Chemotherapy; 2005 Dec 16-19; 93. Hilliard JJ, Melton J, Zhang W, et al. In vivo activity of Washington, DC, 187 doripenem against systemic E. coli infections in the mouse 77. Totsuka K, Kikuchi K. In vitro postantibiotic effect and in vivo [abstract no. 435]. 45th Annual Infectious Diseases Society of antimicrobial activity of doripenem, a new carbapenem [in America; 2007 Oct 4-7; San Diego (CA), 139 Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 52-6 94. Hilliard JJ, Melton J, Zhang W. In vivo activity of doripenem, 78. Nishio H, Komatsu M, Shibata N, et al. Metallo-β-lactamase- imipenem, meropenem, and ceftazidime against systemic producing Gram-negative bacilli: laboratory-based surveil- pseudomonal infections in the mouse [abstract no. 434]. 45th lance in cooperation with 13 clinical laboratories in the Kinki Annual Infectious Diseases Society of America; 2007 Oct 4-7; region of Japan. J Clin Microbiol 2004 Nov; 42 (11): 5256-63 San Diego (CA), 139 95. Sato T, Tsuji M, Okazaki K, et al. Therapeutic efficacy of 79. Deshpande LM, Jones RN, Fritsche TR, et al. Occurrence and doripenem, a novel parenteral carbapenem antibiotic, against characterization of carbapenemase-producing Enterobacter- experimental infection in mice and rats [in Japanese]. Jpn J iaceae: report from the SENTRY Antimicrobial Surveillance Chemother 2005; 53 Suppl. 1: 71-9 Program (2000-2004). Microb Drug Resist 2006; 12 (4): 223- 30 96. Katsube T, Yamano Y, Yano Y. Pharmacokinetic-pharmacodynamic modeling and simulation for in vivo bactericidal effect 80. Okamoto K, Gotoh N, Nishino T. Alterations of susceptibility of in murine infection model. J Pharm Sci 2008 Apr; 97 (4): Pseudomonas aeruginosa by overproduction of multidrug ef- 1606-14 flux systems, MexAB-OprM, MexCD-OprJ, and MexXY/ 97. Hilliard J, Melton J, Zhang W, et al. In vivo anti-pseudomonal OprM to carbapenems: substrate specificities of the efflux activity of doripenem [abstract no. 199]. 44th Annual Infec- systems. J Infect Chemother 2002 Dec; 8 (4): 371-3 tious Diseases Society of America; 2006 Oct 12-15; Toronto 81. Li XZ, Nikaido H. Efflux-mediated drug resistance in bacteria. (ON), 81 Drugs 2004; 64 (2): 159-204 98. Fernandez J, Zhang W, . In vivo activity of doripenem in a 82. Mesaros N, Nordmann P, Plesiat´ P, et al. Pseudomonas aerugi- pseudomonal murine skin infection model [abstract no. 196]. nosa: resistance and therapeutic options at the turn of the new 44th Annual Infectious Diseases Society of America; 2006 Oct millennium. Clin Microbiol Infect 2007 Jan; 13: 560-78 12-15; Toronto (ON) 83. Pumbwe L, Ueda O, Yoshimura F, et al. Bacteroides fragilis 99. Horiuchi M, Kimura M, Tokumura M, et al. Absence of convul- BmeABC efflux systems additively confer intrinsic anti- sive liability of doripenem, a new carbapenem antibiotic, in microbial resistance. J Antimicrob Chemother 2006; 58 (1): comparison with β-lactam antibiotics. Toxicology 2006 May 37-46 1; 222 (1-2): 114-24 84. Pumbwe L, Glass D, Wexler HM. Efflux pump overexpression 100. Floren L, Wikler M, Kilfoil T, et al. A phase 1 open-label in multiple-antibiotic-resistant mutants of Bacteroides fragilis. controlled study to evaluate the safety, tolerability, and Antimicrob Agents Chemother 2006 Sep; 50 (9): 3150-3 pharmacokinetics of doripenem administered intravenously to 85. Sakyo S, Tomita H, Tanimoto K, et al. Potency of carbapenems subjects with renal impairment [abstract no. A-17 plus poster]. for the prevention of carbapenem-resistant mutants of Pseudo- 44th Interscience Conference on Antimicrobial Agents and monas aeruginosa: the high potency of a new carbapenem Chemotherapy; 2004 Oct 30-Nov 2; Washington DC, 4 doripenem. J Antibiot (Tokyo) 2006 Apr; 59 (4): 220-8 101. Nakashima M, Sesoko S, Oguma T. Phase I study of doripenem, 86. Kim SY, Park YJ, Yu JK, et al. Prevalence and mechanisms of a new carbapenem antibiotic for injection, in elderly volun- decreased susceptibility to carbapenems in Klebsiella pneu- teers [in Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 124-9

102. Nakashima M, Oguma T. Phase I study of doripenem, a new multiple bacteria in a murine thigh infection model [abstract carbapenem antibiotic for injection in healthy volunteers [in no. A-308]. 43rd Interscience Conference on Antimicrobial Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 104-23 Agents and Chemotherapy; 2003 Sep 14-17; Chicago (IL), 10 103. Shiba K, Nakashima M. Effect of probenecid on pharmaco- 121. Andes DR, Craig WA, Bhavnani SM, et al. PK-PD evaluation of kinetics of doripenem in healthy male volunteers [in Japanese]. doripenem (DOR) against extended spectrum β-lactamase Jpn J Chemother 2005; 53 Suppl. 1: 136-42 (ESBL) producing Enterobacteriaceae [abstract no. 182]. 41st 104. Uehara S, Murao W, Seno Y, et al. Pharmacokinetics of Annual Meeting of the Infectious Diseases Society of doripenem in patients with renal dysfunction [in Japanese]. Jpn America; 2003 Oct 9-12; San Diego (CA), 59 J Chemother 2005; 53 Suppl. 1: 130-5 122. Ambrose PG, Phillips L, Bhavnani SM, et al. Use of pharmaco- 105. Thye DA, Kilfoil T, Leighton A, et al. Doripenem: a phase 1 kinetics-pharmacodynamics (PK-PD) as decision support for study to evaluate safety, tolerability and pharmacokinetics in a phase 3 dose justification for doripenem [abstract no. A-140]. Western healthy volunteer population [abstract no. A-21 plus 44th Interscience Conference on Antimicrobial Agents and poster]. 43rd Interscience Conference on Antimicrobial Chemotherapy; 2004 Oct 30-Nov 2; Washington DC, 12 Agents and Chemotherapy; 2003 Sep 14 -17; Chicago (IL) 123. Kuroda N, Munekage T, Yamano Y. Bactericidal activity of 106. Ikawa K, Morikawa N, Urakawa N, et al. Peritoneal penetration doripenem using in vitro pharmacodynamic models [in Japa- of doripenem after intravenous administration in abdominal- nese]. Jpn J Chemother 2005; 53 Suppl. 1: 96-103 surgery patients. J Antimicrob Chemother 2007 Dec 1; 60 (6): 124. Kim A, Banevicius MA, Nicolau DP. In vivo pharmacodynamic 1395-7 profiling of doripenem human simulated exposures against 107. Tanimura H, Aikawa N, Sumiyama Y, et al. Pharmacokinetic Pseudomonas aeruginosa. Antimicrob Agents Chemother. profiles and clinical efficacy of doripenem in surgical infection Epub 2008 May 5 [in Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 260-72 125. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis 108. Okada H, Yasuda J, Hirabayashi K, et al. Basic and clinical Campaign: international guidelines for management of severe studies on doripenem in obstetrics and gynecology [in Japa- sepsis and septic shock: 2008 (published erratum appears in nese]. Jpn J Chemother 2005; 53 Suppl. 1: 273-85 Crit Care Med 2008 Apr; 36 (4): 1394-6). Crit Care Med 2008 109. Baba S, Suzuki K, Miyamoto N. A study of distribution of Jan; 36 (1): 296-327 doripenem in otolaryngologic tissues and clinical relevance in 126. Rea-Neto´ A, Niederman M, Lobo SM, et al. Efficacy and safety otolaryngologic infection [in Japanese]. Jpn J Chemother of doripenem versus piperacillin/tazobactam in nosocomial 2005; 53 Suppl. 1: 293-302 pneumonia: a randomized, open-label, multicenter study. Curr 110. Sasaki J, Kaneko A. Clinical studies on doripenem of dentistry Med Res Opin 2008 Jun 11; 24 (7): 2113-26 and oral surgery [in Japanese]. Jpn J Chemother 2005; 53 127. Saito A, Watanabe A, Nakata K, et al. Comparative study of Suppl. 1: 323-31 doripenem and meropenem in respiratory infections. Phase III 111. Ooishi M, Miyanaga Y, Ohno S, et al. Study of doripenem double-blind comparative study [in Japanese]. Jpn distribution in ocular tissue and its clinical relevance in oph- J Chemother 2005; 53 Suppl. 1: 185-204 thalmological infection [in Japanese]. Jpn J Chemother 2005; 128. Saito A, Watanabe A, Odagiri S, et al. A dose-finding study on 53 Suppl. 1: 313-22 doripenem in chronic respiratory tract infection [in Japanese]. 112. Arata J, Watanabe S, Miyachi Y, et al. Laboratory and clinical Jpn J Chemother 2005; 53 Suppl. 1: 169-84 evaluation of doripenem in deep-seated skin infection [in 129. Chastre J, Wunderink R, Prokocimer P, et al. Efficacy and Japanese]. Jpn J Chemother 2005; 53 Suppl. 1: 303-12 safety of intravenous infusion of doripenem versus imipenem 113. Nakajima Y, Mizobuchi M, Nakamura M, et al. Mechanism of in ventilator-associated pneumonia: a multicenter, randomized the drug interaction between valproic acid and carbapenem study. Crit Care Med 2008 Apr; 36 (4): 1089-96 antibiotics in monkeys and rats. Drug Metab Dispos 2004 Dec; 130. Kollef MH, Rello J, Prokocimer P, et al. Efficacy of doripenem 32 (12): 1383-91 in nosocomial pneumonia: non-ventilator-associated and ven- 114. Mori H, Takahashi K, Mizutani T. Interaction between valproic tilator-associated pneumonia [abstract]. Chest 2007 Oct; 132 acid and carbapenem antibiotics. Drug Metab Rev 2007; 39 (4 Suppl.): 498-9s (4): 647-57 131. Lucasti C, Jasovich A, Umeh O, et al. Efficacy and tolerability 115. Van Wart S, Bhavnani SM, Phillips L, et al. Population of IV doripenem versus meropenem in adults with complicated pharmacokinetics of doripenem [abstract no. A-18 plus post- intra-abdominal infection: a phase III, prospective, multicen- er]. 44th Interscience Conference on Antimicrobial Agents and ter, randomized, double-blind, noninferiority study. Clin Ther Chemotherapy; 2004 Oct 30-Nov 2; Washington DC, 4 2008 May; 30 (5): 868-83 116. Johnson & Johnson Pharmaceutical Research and Development 132. Malafaia O, Umeh O, Jiang J. Doripenem versus meropenem for LLC Raritan (NJ). Doribax (doripenem) injection new drug the treatment of complicated intra-abdominal infections [ab- application 22-106. Clinical pharmacology and biopharmaceu- stract no. L-1564b plus poster]. 46th Interscience Conference tics review(s) 2007 Oct 12 [online]. Available from URL: on Antimicrobial Agents and Chemotherapy; 2006 Sep 27-30; http://www.fda.gov.cder/foi/nda/2007/022106TOC.htm [Ac- San Francisco (CA) cessed 2008 May 19] 133. Solomkin JS, Umeh O, Jiang J, et al. Doripenem vs. meropenem 117. Hori T, Nakano M, Kimura Y, et al. Pharmacokinetics and with an option for oral step-down therapy in the treatment of tissue penetration of a new carbapenem, doripenem, intra- complicated intra-abdominal infections [abstract no. L-487 venously administered to laboratory animals. In Vivo 2006 plus poster]. 47th Interscience Conference on Antimicrobial Jan-Feb; 20 (1): 91-6 Agents and Chemotherapy; 2007 Sep 17-20; Chicago (IL) 118. Mouton JW, Touw DJ, Horrevorts AM, et al. Comparative 134. Naber K, Redman R, Kotey P, et al. Intravenous therapy with pharmacokinetics of the carbapenems: clinical implications. doripenem versus levofloxacin with an option for oral step- Clin Pharmacokinet 2000 Sep; 39: 185-201 down therapy in the treatment of complicated urinary tract 119. Bhavnani SM, Hammel JP, Cirincione BB, et al. Use of pharma- infections and pyelonephritis [abstract no. 833 plus poster]. cokinetic-pharmacodynamic target attainment analyses to sup- 17th European Congress of Clinical Microbiology and Infec- port phase 2 and 3 dosing strategies for doripenem. Antimicrob tious Diseases and the 25th International Congress of Chemo- Agents Chemother 2005 Sep; 49 (9): 3944-7 therapy; 2007 Mar 31-Apr 3; Munich 120. Andes DR, Kiem S, Craig WA. In vivo pharmacodynamic 135. Kamidono S, Arakawa S, Hirose T, et al. Double-blind, control- activity of a new carbapenem, doripenem (DOR), against led study to evaluate safety and efficacy of doripenem and

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