1. Introduction

The carbapenems are β-lactam antibacterial agents with a broad spectrum of activity against a wide range of Gram-positive and Gram-negative aerobic bacteria, and against anaerobic bacteria. However, unlike other β-lactam antibacterials, the carbapenems are stable to nearly all β-lactamases.[1–3] Consequently, in an age of increasing resistance to antibacterial agents, carbapenems are an important therapeutic option, particularly in the treatment of serious infections.[1,2] The most widely available carbapenems are imipenem,[1,2,4] meropenem[5–7] and ertapenem.[8,9] Doripenem (Finibax®, Doribax™),Footnote 1 which has a spectrum of activity similar to that of imipenem and meropenem, is the focus of this review. Other, less widely available carbapenems include biapenem[10] and panipenem.[11]

This article reviews the pharmacological properties of doripenem and its clinical efficacy and tolerability as an intravenous agent in the treatment of adults with lower respiratory tract infections (including nosocomial pneumonia), intra-abdominal infections (IAIs), including complicated IAIs (cIAIs), 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 (ENT) infections, sepsis and endocarditis, dental and oral surgical infection, and ophthalmic infection. Doripenem is approved in a broad range of infections in Japan,[12] for use in cIAIs and cUTIs in the US[13] and EU,[14] and in nosocomial pneumonia (including ventilator-associated pneumonia [VAP]) in the EU.[14]

2. Pharmacodynamic Profile

2.1 Mechanism of Action

Doripenem (figure 1) is a carbapenem antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and anaerobes.[3,15] Like other carbapenems, doripenem interferes with cell wall synthesis, inhibiting cell growth and ultimately leading to bacterial cell death.[15]

Fig. 1
figure 1

Chemical structure of doripenem.

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Doripenem readily penetrates bacterial cell walls, binding with and deactivating specific penicillin-binding proteins (PBPs). PBPs 1a, 1b, 2 and 3 are of primary importance because inhibition of these PBPs leads to cell death.[15] In vitro, doripenem shows strong affinity for PBPs 2, 3 and 4 in Pseudomonas aeruginosa,[12,13,15,16] PBPs 2 and 4 in Escherichia coli[12,13,15,16] and PBP 1 in Staphylococcus aureus[12,16] cell walls, with changes in cell morphology (e.g. formation of spherical cells due to inhibition of PBP 2) apparent 1–2 hours after exposure to the drug.[15,17] Doripenem is highly stable to hydrolysis by all serine β-lactamases, and is relatively stable to human recombinant dehydropeptidase-1 (DHP-1),[16,18,19] unlike imipenem[1] or panipenem.[11]

2.2 In Vitro Antibacterial Activity

The focus of this section is the in vitro activity of doripenem against selected pathogens specified in the US,[13] EU[14] and Japanese[12] manufacturer’s prescribing information (see table I for details). In the US, doripenem is indicated for the treatment of cIAI caused by E. coli, Klebsiella pneumoniae, P. aeruginosa, various Bacteroides spp., S. intermedius, S. constellatus and Peptostreptococcus micros, and for cUTI caused by E. coli, K. pneumoniae, Proteus mirabilis, P. aeruginosa and Acinetobacter baumannii.[13] Doripenem is indicated in adults for the treatment of nosocomial pneumonia (including VAP), cIAI and cUTI in the EU,[14] and in a wider range of indications in Japan, including serious lower respiratory tract infections, IAI, cUTI, cSSSI, obstetric and gynaecological infections, serious ENT infections, sepsis and endocarditis, dental and oral surgical infection, and ophthalmic infection.[12] However, in the EU and Japan, specific organisms are not identified for each of these indications.[12,14] Although the spectrum of doripenem antibacterial activity includes numerous pathogens other than those indicated, the efficacy and tolerability of the drug in infections due to these organisms has not been established in well controlled clinical trials, and the clinical significance of such activity is unclear.[13]

Table I
figure Tab1

Selected causative pathogens against which intravenous doripenem is indicated for the treatment of complicated intra-abdominal infections or complicated urinary tract infections (US and EU),[13,14] nosocomial pneumonia (including ventilator-associated pneumonia) [EU][14] and various serious infections in Japan[12]

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Susceptibility data discussed in this section were collected between 1997 and 2007 in large, worldwide surveillance programmes (including the SENTRY[20] and TRUST[21] programmes)[20–32] and numerous smaller studies (including phase III trials of nosocomial pneumonia,[33,34] cIAIs[34,35] or cUTIs,[34,36] and a study in infected diabetic foot wounds[37]),[33–51] and between 1987 and 2006 in Japanese studies.[16,52–66] Some data are only available as abstracts and posters.[20–31,33–36,38,40,65]

In vitro susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) methods for non-Japanese in vitro studies, and Japanese Chemotherapy Society or CLSI methods for Japanese in vitro studies. CLSI breakpoints for doripenem have not yet been established; however, the following breakpoints, which are based on clinical outcomes, are proposed in the US manufacturer’s prescribing information: ≤0.5 mg/L for Enterobacteriaceae, ≤2.0 mg/L for P. aeruginosa, ≤1.0 mg/L for A. baumannii, ≤0.12 mg/L for S. constellatus and S. intermedius, and ≤1.0 mg/L for anaerobes;[13] and in Brown and Traczewski:[39]≤2 mg/L for Enterobacteriaceae, non-fermentative Gram-negative bacilli, Staphylococcus spp. and H. influenzae, and ≤1 mg/L for streptococci. In addition, some studies used a proposed breakpoint of ≤4.0 mg/L for establishing susceptible organisms.[40,44,45,49,51,67] As doripenem-resistant isolates of these organisms have not yet been identified, only susceptibility breakpoints are available in the US.[13,39] Jones et al.[68] have proposed the following possible carbapenem or other β-lactam surrogate agents for doripenem susceptibility testing until doripenem-containing commercial systems are available: oxacillin for methicillin-susceptible S. aureus or coagulase-negative staphylococci; ampicillin for enterococci; meropenem, imipenem or ertapenem for Enterobacteriaceae; meropenem or imipenem for P. aeruginosa and Acinetobacter spp; and ertapenem for H. influenzae and S. pneumoniae. Recent European breakpoints proposed for doripenem are: ≤1 mg/L (susceptible) and >4 mg/L (resistant) against Enterobacteriaceae, Acinetobacter spp. and Pseudomonas spp., and ≤1 mg/L (susceptible) and >1 mg/L (resistant) against Streptococcus spp., S. pneumoniae, Haemophilus spp. and anaerobes. Staphylococcal susceptibility and resistance is inferred from the methicillin breakpoint.[14]

Comparator antibacterial agents shown in tables II–IV were selected because they were the comparator agents in the clinical trials discussed in section 5.

Table II
figure Tab2figure Tab2

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[20] and TRUST[21] programmes)[20–27,32] and various smaller studies[24,28,29,31,33,35–41,44,45,48,51,67] (Japanese studies are shown separately). Pathogens tested were clinical isolates, apart from drug-resistant pathogens in six studies.[28–30,41,44,51] Testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

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Table III
figure Tab3

In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-negative bacteria collected between 1987 and 2006 in Japan.[16,53–58,61,63,65,66] Testing was performed according to the Clinical and Laboratory Standards Institute (CLSI)[16,54,55,58,61,65] or Japanese Society of Chemotherapy[53,56,57,63] methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

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2.2.1 Gram-Negative Bacteria

Doripenem demonstrated good in vitro activity against clinically relevant Enterobacteriaceae, including E. coli, Klebsiella spp., Citrobacter spp., Enterobacter spp., Morganella morganii, Proteus spp. and Serratia spp. (tables II and III). The minimum concentration inhibiting 90% of strains (MIC90) was generally ≤0.5 mg/L (tables II and III) and susceptibility rates, where reported, were 93–100%.[23,26,44,45,51] The exceptions were isolates from two Japanese studies[53,57] (one used isolates from patients with cUTIs[53]) in which MIC90 values were 1.56[57] and 3.13[53] mg/L against E. cloacae, 0.78[53] and 6.25[57] mg/L against P. vulgaris, 0.78 mg/L against P. mirabilis and M. morganii,[53] and 6.25 mg/L against S. marcescens,[53,57] and two US studies of selected clinical isolates[39,41] in which the MIC90 against P. mirabilis was 1 mg/L.

Doripenem showed good activity against extended-spectrum β-lactamase (ESBL)-producing, AmpC-producing (ceftazidime-intermediate/resistant), or fluoroquinolone-resistant Enterobacteriaceae.[20,23,29,32–34,36,41,44,47,51] For example, doripenem MIC90 values did not differ between non-ESBL-producing and ESBL-producing E. coli, K. pneumoniae or P. mirabilis isolates (table II); however, in one Japanese study[59] the minimum inhibitory concentration (MIC) was 32 mg/L against one class B ESBL-producing strain of E. coli. Doripenem also retained good antibacterial activity against both AmpC-producing and non-AmpC-producing strains of Enterobacter spp. and S. marcescens (MIC90 ≤0.5 vs ≤0.12 mg/L; susceptibility rates of 100%).[41,51] In one study,[41] the MIC value was 2 mg/L against AmpC-producing P. mirabilis.

Doripenem activity against carbapenemase-producing Klebsiella or Serratia spp. was limited, with MIC90 values of 8 to >64 mg/L.[47]

Doripenem was active against the respiratory pathogens H. influenzae and Moraxella catarrhalis (MIC90 ≤1.56 mg/L), and against Providencia spp. (MIC90 ≤1.56 mg/L), although the MIC90 for the β-lactamase non-producing, ampicillin-resistant strains of H. influenzae was 2–3.13mg/L (tables II and III).

Doripenem was active against P. aeruginosa isolates across all geographic areas (MIC90 0.2–12.5 mg/L; tables II and III) [where evaluated, 87–100% susceptibility[26,45,51] ], including ceftazidime- or imipenem-susceptible[28] or non-multidrug-resistant[38] isolates (MIC90 of 2–4 mg/L) obtained from hospital inpatients in the US[38] or Europe,[28] and ceftazidime- or imipenem-susceptible or ceftazidime-resistant Japanese isolates (including PER-1-type ESBL-producing P. aeruginosa[52]) [MIC90 ≤4 mg/L].[52,58,63] However, doripenem had poor activity against metallo-β-lactamase-producing or ceftazidime-, imipenem- or multidrug-resistant P. aeruginosa isolates evidenced by MIC90 values of 8–64 mg/L (tables II and III) and, where reported, susceptibility rates of 22–40%.[40,51,67]

Compared with activity against the parent wild-type strain, doripenem activity was increased against P. aeruginosa mutants lacking mexAB-oprM[58,62] (probably due to reduced expression of AmpC β-lactamase[62]), and virtually unchanged against mutant strains of P. aeruginosa (OprD deficiency [reduced porin production] and overexpression of mexAB-oprM or mexEF-oprN [increased efflux pump activity]), with MIC90 values of 1.0 versus 0.5 mg/L.[58] However, the activity of other carbapenems was reduced against strains that had the combination of porin deficiency and increased efflux pump activity (by up to 4-fold for meropenem, up to 8-fold for imipenem and up to 16-fold for biapenem).[58]

Doripenem showed limited activity against Acinetobacter spp. (including A. baumanii) in studies in Europe and the Americas, regardless of whether isolates were susceptible or ceftazidime-intermediate or -resistant (MIC90 1–32 mg/L; table II) [where reported, susceptibility rates 76–78%[26,45,51] ] or carbapenemase- or metallo-β-lactamase-producing (MICs 16–32 mg/L).[47] The MIC90 values for Acinetobacter spp. isolated in Japan were ≤3.13 mg/L (table III).

The antibacterial activity of doripenem against Gram-negative pathogens, including P. aeruginosa and E. coli, was not affected by inoculum size.[16,70]

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-susceptible isolates), Streptococcus pneumoniae (including 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 100%.[25,27,44,45] However, S. epidermidis susceptibility to doripenem varied according to geographic region, with MIC90 values of 0.03 mg/L (methicillin- or oxacillin-susceptible isolates) and 4 mg/L (oxacillin resistant) in Europe and the Americas (table IV) compared with MIC90 values of ≤0.031–12.5mg/L (methicillin susceptible) and 8–50 mg/L (methicillin resistant) in Japan (table V).

Table IV
figure Tab4

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)

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Table V
figure Tab5

In vitro activity of doripenem (DOR) and other antibacterials against aerobic Gram-positive bacteria collected between 1987 and 2006 in Japan.[16,53–55,57,63,65,66] Testing was generally performed according to the Clinical and Laboratory Standards Institute (CLSI)[16,54,55,65,66] or Japanese Society of Chemotherapy[53,57,63] methods. Data shown are minimum concentrations inhibiting 90% of strains (MIC90)

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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 Enterococcus faecalis (MIC90 4–16 mg/L) and poor activity against other Enterococci, including E. faecium (MIC90 >32 to >128 mg/L) [table IV and table V].

The antibacterial activity of doripenem against Gram-positive pathogens, including S. aureus, was not affected by inoculum size.[16,70]

2.2.3 Anaerobic Bacteria

Doripenem showed good activity against a range of anaerobic bacteria (tables VI and VII), although regional variations in susceptibility were evident. For instance, doripenem MIC90 values against B. fragilis isolates from Europe and the Americas were 0.25–1 mg/L (susceptibility rates of 96–100%[45,49]), whereas MIC90 values against Japanese isolates were 0.78–2mg/L (table VI and table VII). Likewise, for Peptostreptococcus spp., the doripenem MIC90 was 0.25 mg/L against European and American isolates, and 0.063–6.25mg/L against Japanese isolates (table VI and table VII). Doripenem also showed activity against toxigenic C. difficile clinical isolates (MIC90 2 mg/L); the meropenem MIC90 against these isolates was also 2 mg/L.[42]

Table VI
figure Tab6

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)

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Table VII
figure Tab7

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)

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2.2.4 Synergistic Activity

Little antagonistic potential has been observed in in vitro synergy tests with doripenem and amikacin, cotrimoxazole, daptomycin, levofloxacin, linezolid, vancomycin, teicoplanin or ceftobiprole.[13,72–74]

Preliminary data suggest a strong synergistic effect in vitro between the investigational metallo-β-lactamase inhibitor CP 3242 and carbapenems, including doripenem, against some carbapenemase-producing pathogens [reported as an abstract].[75] For instance, MIC values against an IMP-1-producing P. aeruginosa strain, which were 8 mg/L for doripenem and ≥256 mg/L for imipenem or meropenem, were reduced to 1 mg/L for doripenem and 0.5 mg/L for imipenem or meropenem in the presence of 32 g/L of CP 3242 using broth dilution methods.[75] Likewise, in the presence of CP 3242, MIC values against an IMP-2-producing A. baumanii strain were reduced from 16 mg/L to 1 mg/L for doripenem, 128 mg/L to 1 mg/L for imipenem and >256 mg/L to 2 mg/L for meropenem. Synergistic effects between the carbapenems and CP 3242 against VIM-1- or VIM-2-producing P. aeruginosa strains were not as pronounced (MIC values were 0–16 times [VIM-1] and 0–4 times [VIM-2] lower).[75]

2.2.5 Bactericidal Activity and Post-Antibiotic Effect

Doripenem exhibited rapid, time-dependent bactericidal activity against P. aeruginosa (including an efflux pump over-expressing strain),[58,70,76] E. coli[70] and S. aureus.[70] For instance, a 3–4 log10 reduction in the P. aeruginosa bacterial count was observed over 6–8 hours with doripenem at 2–8 × the MIC.[76] For most strains, killing was only slightly more rapid and extensive at 8 × the MIC than at 2 or 4 × the MIC.[76] The mean MBC : MIC ratio against 20 clinical strains of P. aeruginosa was 1.5 for doripenem, 1.25 for meropenem and 1.7 for imipenem, indicating strong bactericidal activity.[58] In contrast, the mean MBC : MIC ratio for ceftazidime was 2.45.[58]

Doripenem also showed bactericidal activity (99.9% kill) against various clinically relevant anaerobes (e.g. B. fragilis, B. thetaiotaomicron and P. intermedia) at 2 × the MIC after 48 hours.[43]

Doripenem demonstrated an in vitro post-antibiotic effect (PAE) of 1.9 hours against S. aureus, 1.8–2 hours against P. aeruginosa, 0.3–0.5 hours against E. coli and 0.3 hours against K. pneumoniae (all assessed at 2 or 4 × the MIC).[70,77]

2.3 Resistance Issues

Doripenem shows stability against hydrolysis by most β-lactamases, including AmpC β-lactamase and ESBLs.[16,32] As discussed in section 2.2.1, there was little change in MIC90 values in comparisons of wild-type and ESBL-producing E. coli or K. pneumoniae isolates, or wild-type and AmpC-producing Enterobacter spp. or S. marcescens.[32,51] However, carbapenemases can affect the activity of doripenem.[78] Among the most potent carbapenemases are the class B metallo-β-lactamases,[78] the production of which is intrinsic in S. maltophilia, thus resulting in resistance to doripenem,[32] but can also be acquired by P. aeruginosa and other Gram-negative species.[78,79] Although carbapenemases are still uncommon, carbapenemase-producing Gram-negative pathogens are being reported with increasing frequency.[78]

Other potential resistance mechanisms that can confer resistance to β-lactam antibacterial drugs include alteration of PBPs leading to poor binding affinity (present in bacteria such as Enterococcus spp. and methicillin- or oxacillin-resistant S. aureus [MRSA]), overexpression of multidrug efflux pumps limiting drug accumulation at target sites (detected in some Gram-negative bacteria, including P. aeruginosa[80–82] and B. fragilis[83,84]) and reduced membrane permeability due to loss of OprD, and thus a reduction in porins, in bacterial cell walls.[46,79,81,82]

In in vitro studies, the loss of OprD in P. aeruginosa isolates increased doripenem, meropenem and imipenem MICs.[46] Increasing carbapenem resistance in P. aeruginosa isolates as a result of the overexpression of efflux pumps (including MexAB-OprM) has been documented;[80] doripenem and meropenem MICs were increased in such mutants, whereas imipenem MICs were not affected.[46,80] Nevertheless, a combination of resistance mechanisms, such as the presence of carbapenemases and reduced permeability, or overexpression of multidrug efflux pumps and reduced permeability, is required for significant carbapenem resistance to emerge.[46,85] For example, detectable doripenem resistance in K. pneumoniae isolates[86] requires the presence of both reduced permeability and the presence of a carbapenemase, and reduced permeability and a functional AmpC β-lactamase are required for doripenem resistance in P. aeruginosa isolates[46] (see also section 2.2). Multiple resistance mechanisms are also required for detectable meropenem resistance in P. aeruginosa isolates; in contrast, OprD loss alone may confer resistance to imipenem.[46]

In vitro studies in which characterized AmpC-inducible strains or wild-type clinical isolates of Enterobacteriaceae or P. aeruginosa were exposed to various antibacterial agents (including doripenem, meropenem or imipenem) at 0.5 or 1 times the MIC, revealed differences between the carbapenems in inducing genes associated with resistance.[87,88] For instance, imipenem induction of AmpC β-lactamases was at least 2-fold higher than that of doripenem or meropenem, whereas doripenem and meropenem had similar induction profiles.[87,88] In one of the studies, imipenem induction of porin gene expression was stronger than that seen with doripenem.[87]

Mucoid strains of P. aeruginosa (as opposed to flagellar strains) produce large quantities of exopolysaccharide alginate, which is associated with the evasion of phagocytosis at the site of infection, protection against reactive oxygen intermediates and reduced susceptibility to antibacterial agents.[89] Various studies have suggested that exposure of P. aeruginosa isolates to subinhibitory concentrations of β-lactam antibacterials may increase alginate production (and therefore reducing antibacterial efficacy) by upregulating alginate-producing gene expression.[90] In planktonic cultures of wild-type P. aeruginosa exposed to imipenem, doripenem or meropenem at concentrations 1 times the MIC, alginate biosynthetic operon expression and synthesis was generally unaffected by doripenem or meropenem, whereas with imipenem, alginate biosynthetic operon expression and synthesis was upregulated (p < 0.01 for imipenem vs doripenem) and flagellar gene expression was reduced.[91] Of interest, the response to imipenem was considered to be similar to the phenotype of mucoid strains of P. aeruginosa that are associated with increased mortality in cystic fibrosis patients.[91]

Doripenem generally appears to have a low potential for selecting resistant strains in vitro.[12,13,46,85,92] A study comparing the potencies of doripenem, meropenem and imipenem in preventing the emergence of carbapenem-resistant mutants of P. aeruginosa, found that mutants with decreased or no expression of the outer membrane protein OprD were predominantly selected; relative potencies were doripenem > imipenem > meropenem.[85] Serial passaging studies showed that the combination of doripenem plus an aminoglycoside (gentamicin) was more potent than doripenem alone in preventing selection of resistant P. aeruginosa strains during the first three passages, although MIC values increased 2- to 4-fold during the seven-passage study.[92] Although potential exists for cross-resistance to carbapenem-resistant isolates to develop (decreased susceptibility of S. aureus, E. coli and P. aeruginosa to doripenem, meropenem or imipenem with cross-resistance was seen in a serial passaging study [14 passages[16] ]), some carbapenem-resistant pathogens may be susceptible to doripenem.[12,13]

2.4 In Vivo Antibacterial Activity

In murine models of immunocompetent or neutropenic Gram-negative systemic, respiratory, UTI or skin infection,[52,58,63,70,93–98] or Gram-positive systemic or lung infection,[63,70,95] and rat models of penicillin-resistant pneumococcal meningitis, S. aureus endocarditis or polymicrobial intrauterine infection (E. coli and B. fragilis pyometra),[54] doripenem was generally at least as effective as imipenem/cilastin, meropenem/cilastin, biapenem, cefotaxime or cefpirome, and more effective than ceftazidime, cefepime, ampicillin or piperacillin/tazobactam.[52,54,58,63,70,93–98]

Gram-negative organisms studied included K. pneumoniae, P. vulgaris, H. influenzae (including β-lactamase-producing strains), P. aeruginosa (including a PER-1-type ESBL-producing strain and ceftazidime-, imipenem- or multidrug-resistant strains), A. calcoaceticus, wild-type or β-lactamase-producing strains of E. coli, and ceftazidime-resistant strains of E. cloacae and S. marcescens. Gram-positive organisms studied included S. aureus, S. pyogenes, S. pneumoniae (including penicillin-resistant strains) and E. faecalis. Antibacterial activity was assessed using the dose of drug resulting in the survival of 50% of animals[52,58,63,70,93–95,97] or skin lesion volume and/or bacterial cell count in fluid.[54,63,95,98]

The effective bacterial regrowth time in a murine neutropenic thigh infection model was 7.8 hours against S. aureus and 5 hours against K. pneumoniae after administration of doripenem 50 mg/kg and 8 hours against P. aeruginosa after a 100 mg/kg dose.[77]

In a neutropenic mouse P. aeruginosa lung infection model, the doripenem PAE after a 3 mg/kg dose was 6.12 hours, compared with 5.9 and 3.49 hours for meropenem/cilastin or imipenem/cilastin 3 mg/kg and 0.35 hours for ceftazidime 10 mg/kg.[58]

2.5 Other Effects

Doripenem showed no convulsive activity in in vivo studies in rats, mice or dogs, nor did it have an effect on the anticonvulsant activity of valproic acid in a rat pentylenetetrazol- or bicuculine-induced convulsive model.[99]

3. Pharmacokinetic Properties

The pharmacokinetics of intravenous doripenem after single-[100–104] or multiple-[102,105] dose administration has been assessed in healthy US[105] or Japanese adult volunteers,[102,103] in elderly Japanese[12,101] or US[13] volunteers, and in US[100] or Japanese[12,104] individuals with renal impairment. Tissue penetration of doripenem after intravenous administration has been assessed in a number of studies in Japanese patients.[64,106–112] Drug interaction data for doripenem and valproic acid are from animal studies[113] and case reports.[114] Data from the US,[13] EU[14] and Japanese[12] manufacturer’s prescribing information are supplemented by results from individual pharmacokinetic studies[64,100–112] or analyses,[115] and the manufacturer.[116] Some data[100,105,115] are only available as abstracts and posters.

3.1 Distribution

The pharmacokinetics of doripenem are linear over a dose range of 125–1000 mg, infused over 30 or 60 minutes either as a single dose[102,115] or as a 500 or 1000 mg dose administered two or three times daily for 1–7 days,[102,105] or over 4 hours[14] in both Japanese[102] and non-Japanese[14,105,115] studies, with no evidence of accumulation. Plasma doripenem concentrations are best described by a two-compartment model, according to a population pharmacokinetic model that used data from healthy adult volunteers (n = 24), individuals with renal impairment (n = 20) and patients with cUTIs (n = 107).[115] Mean peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) values after a single dose of doripenem 250 or 500 mg administered as a 1-hour infusion in healthy non-Japanese or Japanese adults are shown in table VIII.

Table VIII
figure Tab8

Pharmacokinetics of intravenous doripenem (DOR) after 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-Japanese[13,14] adults. Values are means, unless stated otherwise

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After prolonged (4-hour infusion) intravenous administration of doripenem 500 mg or 1 g in healthy volunteers, mean Cmax values were ≈8 and ≈17 μg/mL, and mean AUC values from time zero to infinity were ≈34 and ≈68 μg ⋅ h/mL.[14]

Plasma protein binding of doripenem is low (≈8%) and is independent of plasma drug concentrations.[13,14] Doripenem distributes into a wide variety of tissues, with a median volume of distribution (Vd) at steady state of 16.8 L, consistent with distribution into the extracellular space.[13] Doripenem penetrates tissues well, and achieves drug concentrations at or above those required to inhibit most susceptible bacteria, although the clinical significance of this finding in retroperitoneal fluid and peritoneal exudate is not established.[13] After a single intravenous dose of 250 or 500 mg, doripenem concentrations were detected in most tissues and/or fluids, including retroperitoneal fluid, peritoneal exudate, gallbladder tissue, bile, urine, dermal tissues, synovial fluid, bone, sputum, prostatic tissue, gynaecological tissues, middle ear mucosa and middle ear secretions, palatine tonsil tissue, aqueous humour, gingival tissue and various cysts.[12–14,64,106–112] Animal studies have shown that after intravenous administration, doripenem is also distributed extensively in the kidney, liver, lung, heart and spleen.[117]

3.2 Metabolism and Elimination

Doripenem is metabolized via DHP-1 to a microbiologically inactive metabolite. Most of a dose of doripenem is not metabolized, as the drug is relatively stable to DHP-1.[13,14] In a study of prolonged-infusion regimens, the mean plasma doripenem metabolite : doripenem AUC ratio was 13% after a single dose of doripenem 500 mg administered over 4 hours and 18% after a single dose of doripenem 1000 mg administered over 4 hours.[116] In vitro studies have shown that doripenem does not undergo metabolism by, and is therefore not a substrate for, hepatic cytochrome P450 (CYP) isoenzymes. During a period of 1 week after administration of a single 500 mg dose of radiolabelled doripenem in healthy volunteers, <1% of the total radioactivity was recovered in faeces.[13]

Doripenem is primarily excreted as the unchanged drug via the kidneys;[12,14] the high renal clearance rate (table VIII) and the significant reduction in doripenem elimination when the drug coadministered with probenecid (section 3.4), suggest that doripenem undergoes both active tubular secretion and glomerular filtration. Urinary elimination is not dose dependent,[12] and 85–90% of a dose is excreted (70–75% as the unchanged drug) within 24–48 hours of administration.[12,13]

3.3 Special Patient Populations

The pharmacokinetics of intravenous doripenem are not affected by age, ethnicity or gender.[12–14] The effect of hepatic impairment on the pharmacokinetics of doripenem has not been studied, but is thought to be of no clinical consequence, because the drug does not undergo hepatic metabolism.[13,14] The pharmacokinetics of doripenem in patients with severe infections or sepsis are not available.

3.3.1 In Renal Impairment

As a result of prolongation of the doripenem terminal elimination half-life (t½β) in patients with renal impairment,[12,100,104] systemic exposure to doripenem is significantly increased in these patients.[12–14,104] In Japanese individuals, mean AUC values after intravenous administration of a single 250 mg dose of doripenem, t½β values in patients with mild (creatinine clearance [CLCR] 50 to <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 <30 mL/min [<1.8 L/h]) renal impairment were increased 2.2- to 4.0-fold compared with that in healthy volunteers (1.98, 2.16 and 3.56 vs 0.9 hours) and AUC values were increased 2.0- to 3.2-fold (40.55, 48.21 and 64.31 vs 20.26 μg ⋅ h/mL).[104]

Likewise, in non-Japanese individuals, mean AUC values after intravenous administration of a single 500 mg dose of doripenem were increased 1.6-fold in patients with mild renal impairment (CLCR 50–79 mL/min [3.0–4.74 L/h]), 2.8-fold in those with moderate renal impairment (CLCR 31–50 mL/min [1.86–3.0 L/h]) and 5.1-fold in those with severe renal impairment (CLCR ≤30 mL/min [≤1.8 L/h]) compared with aged-matched individuals with normal renal function.[13,14] Dosage adjustments are required in patients with moderate or severe renal impairment (see section 7).[12–14]

In patients with end-stage renal disease undergoing haemodialysis (doripenem was administered post-dialysis), the mean doripenem AUC was increased 7.8-fold compared with individuals with normal renal function; 52% of a dose of doripenem was recovered in dialysate (46% as the unchanged drug and 6% as the metabolite[116]) after a 4-hour haemodialysis session.[13,116] Insufficient data are available for dosage adjustment recommendations in this group of patients.[13]

3.4 Potential Drug Interactions

As doripenem is not metabolized via CYP isoenzymes (section 3.2), it is not expected to inhibit clearance of drugs metabolized via these pathways or to induce these isoenzymes in a clinically relevant manner.[13,14]

When administered concomitantly with probenecid, doripenem elimination decreased, evidenced by a significantly prolonged t½β (p = 0.0002 vs doripenem alone) and significant reductions in systemic and renal clearance, and cumulative urinary excretion of doripenem (all p < 0.01).[103] As a consequence, systemic exposure to doripenem (Cmax and AUC) was significantly increased (both p < 0.01).[103] The concomitant administration of doripenem and probenecid is not recommended.[12–14]

When carbapenems are administered concurrently with valproic acid, serum valproic acid concentrations may be reduced to subtherapeutic levels with subsequent loss of seizure control.[12–14] Consequently, coadministration of doripenem and valproic acid is contraindicated in Japan,[12] and requires frequent monitoring of serum valproic acid concentrations in the US[13] and EU.[14] The mechanism of interaction is not understood, but results of animal and in vitro studies suggest that carbapenems may inhibit valproic acid glucuronide hydrolysis.[113,114]

4. Pharmacodynamic/Pharmacokinetic Relationship

Animal models have shown that for time-dependent antibacterials, such as the carbapenems, the pharmacodynamic/pharmacokinetic parameter that best correlates with bactericidal activity (and therefore efficacy) is the proportion of the dose administration interval that unbound drug concentrations are maintained above the MIC (%T > MICfree).[118–120] A T > MICfree of 30–40% is thought to be sufficient for carbapenems,[118] including doripenem.[119,120] Murine neutropenic thigh infection models showed that achieving a mean T > MICfree of 21–43% produced a 1 or 2 log reduction in bacterial count for S. pneumoniae, S. aureus or Gram-negative bacilli (including ESBL-producing Enterobacteriaceae).[120,121]

A Monte Carlo simulation[120] used these pharmacodynanamic/pharmacokinetic targets and a doripenem population pharmacokinetic model (based on pharmacokinetic data from 24 healthy volunteers receiving a single intravenous 500 mg dose of doripenem [data are shown in table VIII]) as inputs to identify potential doripenem dose administration regimens for phase II and phase III clinical studies.[119] A regimen of doripenem 500 mg administered over 60 minutes every 8 hours was predicted to be effective against bacterial isolates with MICs ≤2 mg/L, based on a 99–100% probability of achieving a T > MICfree of 35% for doripenem MIC values of 1 or 2 mg/L.[119] For pathogens with an MIC of >2 mg/L, prolonged (4-hour) infusions of doripenem 500 mg every 8 hours or 1000 mg every 12 hours (MIC 4 mg/L) or doripenem 1000 mg every 8 hours (MIC 8 mg/L) was predicted to be effective, based on a 100% probability of achieving a T > MICfree of 35%.[119] Prolonging the infusion duration increased the period over which doripenem concentrations exceeded MIC.[119] Estimates generated from a simulation predicting pharmacodynanamic/pharmacokinetic target attainment in individuals with normal or impaired renal function, using the same pharmacodynanamic/pharmacokinetic data were consistent with these results.[122]

In another murine neutropenic thigh infection model, a simulated regimen of doripenem 250 mg twice daily infused over 30 minutes was bactericidal for E. coli, S. aureus and P. aeruginosa clinical isolates with MICs ≤0.5 mg/L.[123] This dosage regimen achieved a T > MICfree of >35%, and bactericidal activity did not increase significantly when the T > MICfree increased to >40% (simulated treatment regimens of doripenem 500 mg twice daily or 250 mg three times daily infused over 30 minutes). Against P. aeruginosa strains with an MIC of 1 mg/L, simulated regimens of doripenem 250 mg three times daily or 500 mg twice daily administered over 30 minutes were required to achieve an adequate T > MICfree (33–42%).

However, against P. aeruginosa strains with an MIC of ≥2 mg/L, more frequent administration was necessary to achieve an adequate T > MICfree value.[123] For instance, a simulated regimen of doripenem 250 or 500 mg three times daily administered over 30 minutes achieved a T > MICfree of 31–38% against strains with an MIC of 2 mg/L, whereas a simulated doripenem 500 mg twice-daily regimen only achieved a T > MICfree of 25%. Against strains with an MIC of 3 mg/L, a simulated regimen of doripenem 500 mg three times daily administered over 30 minutes achieved a T > MICfree of 27%.[123] An increase in dose administration frequency, rather than dose per administration was associated with a more prolonged T > MICfree value and greater bactericidal activity.[123]

A murine neutropenic thigh model of P. aeruginosa infection was used to simulate the T > MICfree value for a regimen of intravenous doripenem 500 mg infused over 1 or 4 hours every 8 hours.[124] The simulated 1-hour infusion regimen was bactericidal for P. aeruginosa isolates with an MIC ≤2 mg/L, but had variable kill for isolates with MICs of 4–8 mg/L. Bactericidal activity was maximal once T > MICfree was ≥40% and bacteriostatic activity occurred when T > MICfree was ≈20–30%. The simulated 4-hour infusion regimen was bactericidal for all P. aeruginosa isolates with an MIC ≤2 mg/L and for two of four isolates with MICs of 4 mg/L.[124] The option to administer doripenem as an extended 4-hour infusion in patients with nosocomial pneumonia (including VAP) in the EU prescribing information (section 7) is based on these results.[14]

Although doripenem Cmax values in peritoneal exudate were half those in serum after a single 500 mg 30-minute intravenous fusion in ten patients undergoing abdominal surgery (25 vs 47 mg/L), time to Cmax values in peritoneal exudate were increased by 40% (0.7 vs 0.5 hours).[106] The mean T > MICfree in peritoneal fluid was 78% for an MIC of 1 mg/L and 42% for an MIC of 4 mg/L, confirming that doripenem 500 mg every 8 hours was an adequate treatment regimen to achieve bactericidal activity against common pathogens associated with intra-abdominal infections[106] (e.g. E. coli [MIC90 ≤0.015–0.1 mg/L; section 2.2.1], Streptococcus spp. [MIC90 ≤0.004–1 mg/L; section 2.2.2] and B. fragilis [MIC90 0.25–2; section 2.2.3]).

A limitation of the Monte Carlo and other simulations discussed in this section is that the pharmacokinetic parameters were based on data from healthy volunteers and may not apply to patient populations who have pharmacokinetics that differ significantly from those studied.[119,124] For instance, patients with severe sepsis or septic shock have pharmacokinetic profiles that differ markedly from healthy volunteers or less critically ill patients, because of aggressive fluid resuscitation, the loss of endothelial barrier function (capillary leak syndrome), renal or hepatic impairment and decreased tissue perfusion resulting from impaired cardiocirculatory function.[125]

5. Therapeutic Efficacy

The therapeutic efficacy of doripenem in the treatment of adult patients (mean age 50–59 years) with lower respiratory tract infections (including nosocomial pneumonia),[126–130] cIAIs[131–133] or cUTIs (including complicated or uncomplicated pyelonephritis)[134,135] has been evaluated in eight randomized, multicentre, phase II or III clinical studies. Several smaller, noncomparative studies in Japanese patients with lower respiratory tract infections,[136] IAIs,[107,136,137] cUTIs,[137–139] skin and skin structure infection,[112] obstetric and gynaecological infection,[108] sepsis and endocarditis,[140] ENT infection,[109,136] dental and oral surgery,[110] and ophthalmic infection[111] are also available. Three non-Japanese studies[126,129,131] are fully published, and a further three[130,132,134] are only available as abstracts and posters. All Japanese studies[107–112,127,128,136–140] are fully published.

Primary efficacy endpoints in the randomized trials related to clinical and/or microbiological response rate, generally assessed at the test-of-cure visit.[126–129,131,132,134,135] Seven of the randomized studies[126,127,129,131,132,134,135] determined the noninferiority of doripenem versus active comparators; however, only six studies specified the criterion for noninferiority: a lower limit of the two-sided 95% confidence interval for the between-group difference in clinical[127,131,132,135] or microbiological[134] cure rate (doripenem minus active comparator) of greater than or equal to −10%,[127,134,135]−15%[131,132] or −20%.[126,129]

The Japanese studies generally used doripenem dosages of 250 mg twice[107–112,127,135–139] or three times[107–111,128,136,137] daily, or 500 mg twice[107–112,128,135–141] or three times[140,141] daily infused over 30–60 minutes. The other clinical studies with doripenem utilized a dosage regimen of 500 mg every 8 hours (infused over 60 minutes),[126,131,132,134] with the exception of one study in patients with nosocomial pneumonia in which doripenem 500 mg every 8 hours was infused over 4 hours.[129]

5.1 Serious Lower Respiratory Tract Infections

The efficacy of intravenous doripenem in patients with serious lower respiratory tract infections has been investigated in four randomized, multicentre trials:[126–129] a double-blind, Japanese, dose-finding study of doripenem 250 or 500 mg twice daily,[128] a double-blind, Japanese, noninferiority comparison of doripenem 250 mg or meropenem 500 mg twice daily[127] (both in patients with chronic respiratory disease and concurrent, acute bacterial respiratory infection[127,128]) and two nonblind, international, noninferiority trials comparisons of doripenem versus imipenem/cilastin or piperacillin/tazobactam in patients with nosocomial pneumonia[126,129] (one study only enrolled patients with VAP[129]). Results of three small, noncomparative, Japanese studies of doripenem 250 mg two or three times daily, or 500 mg twice daily (in chronic respiratory disease or community-acquired pneumonia [CAP])[136,137] and doripenem 500 mg two or three times daily, 1 g twice daily or 500 mg twice daily titrated down to 250 mg twice daily based on symptom improvement and age (in nosocomial pneumonia)[141] are also discussed briefly. Treatment duration varied between 3 and 15 days.[126–129,136,137,141]

In the two nonblind international trials (section 5.1.1), doripenem 500 mg three times daily[126,129] (the trial in patients with VAP used a 4-hour rather than the standard 1-hour infusion[129]) was compared with imipenem/cilastin 500 mg four times daily or 1000 mg three times daily in one study,[129] or piperacillin/tazobactam 4.5 g four times daily in the other study.[126] A pooled analysis of these data (available as an abstract)[130] and an assessment of hospital resource utilization in the comparison between doripenem and imipenem/cilastin[142] have been performed. Randomization in both trials was stratified by geographic region,[126,129] disease severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score ≤15 or >15),[126,129] the presence or absence of VAP[126] and/or the duration of mechanical ventilation (<5 or ≥5 days).[129] Both trials recommended coadministration of an aminoglycoside[126,129] (amikacin[129]) [in suspected P. aeruginosa infection] or vancomycin[126,129] (in suspected MRSA infection) where required. Patients in the study that compared doripenem with piperacillin/tazobactam[126] could be switched to oral levofloxacin 750 mg once daily after 3 days of intravenous therapy (9 doses of doripenem and 12 doses of piperacillin/tazobactam).

Patients in the VAP study were required to meet the clinical and radiological criteria for VAP, have a Clinical Pulmonary Infection Score of ≥5 and either have been mechanically ventilated for >24 hours or weaned from mechanical ventilation within the previous 24 hours.[129] At baseline in the clinically evaluable population (per-protocol evaluable; n = 248[129]), 48% of patients in the VAP study had APACHE II scores ≤15, 10% of patients were bacteraemic, 39% had early onset VAP (<5 days) and 19% had renal impairment (CLCR <4.8 L/h [<80 mL/min]).[129] In the other study (n = 253 clinically evaluable patients),[126] 75% of patients had APACHE II scores ≤15, 10% of patients were bacteraemic, 22% had early onset VAP (<5 days) and 44%[126] had renal impairment (CLCR <4.8 L/h [<80 mL/min]).

In the randomized, double-blind, Japanese trials, clinical efficacy statistical analyses were primarily conducted in the per-protocol population, supported by results in the modified intent-to-treat (mITT) population.[127,128] In the noninferiority trial, only patients with moderate, non-MRSA lower respiratory tract infection who complied with the treatment protocol were eligible for inclusion in the clinical efficacy per-protocol analysis (n = 96 doripenem and 97 meropenem recipients).[127] Chronic respiratory disease included chronic bronchitis, bronchiectasis, asthma, emphysema, pulmonary fibrosis or previous pulmonary tuberculosis.[127] Diagnoses included bacterial pneumonia (n = 131) or chronic respiratory disease with concurrent, acute respiratory infection (n = 62). Underlying disease or complications were present in 85% of patients and 38% had already been treated with another antibacterial agent.[127]

In all Japanese trials, clinical efficacy refers to percentages of patients with ‘excellent’ or ‘good’ clinical responses,[128,136,137]‘clinical cure’[141] or ‘effective’ treatment.[127,128]

Co-primary efficacy endpoints in the nonblind, international trials were clinical cure rates at the test-of-cure (TOC) visit (7–14 days after the cessation of therapy in the VAP study[129] or 6–20 days after the cessation of therapy in the comparison with piperacillin/tazobactam[126]) in the clinically evaluable[126,129] and clinical mITT (patients who met the definition of the respiratory tract infection being studied and received any amount of the study drug [n = 501;[129] n = 429[126] ]) populations.

In all trials,[126–129,136,137,141] bacteriological response, which included eradication or presumed eradication of pathogens isolated at baseline, was assessed in the microbiologically evaluable population (defined in one trial[129] as the clinically evaluable population who had at least one baseline pathogen that was susceptible or of intermediate susceptibility to the study drug).

The most frequent causative pathogens isolated at baseline were S. pneumoniae,[127–129,136] other Streptococcus spp.,[129] H. influenzae,[127–129] P. aeruginosa,[126,129,136] S. aureus,[126,129] K. pneumoniae[126,129] and E. cloacae.[126,129] In the randomized trials of nosocomial pneumonia,[129] 13% of P. aeruginosa isolates were resistant to imipenem/cilastin,[129] while 27% of P. aeruginosa and 44% of K. pneumoniae isolates were resistant to piperacillin/tazobactam.[126] Few P. aeruginosa isolates (none in the comparison with imipenem/cilastin[129] and 8% in the comparison with piperacillin/tazobactam[126]) and no K. pneumoniae isolates[126] were resistant to doripenem. Most (≥64%) S. aureus isolates were methicillin susceptible.[126,129]

A dose-finding trial found that doripenem 250 mg twice daily was the optimal dosage in Japanese patients with moderately severe chronic respiratory infection.[128] Clinical efficacy rates with doripenem 250 mg twice daily or 500 mg twice daily at the end-of-treatment (EOT) visit were 100% and 88% in the per-protocol population (n = 36 and 34) and 89% and 84% in the mITT population (n = 44 and 38); no significant between-group differences was evident. Likewise, there was no significant difference in bacterial eradication rates between the two treatment groups (94.1% vs 89.5%; n = 17 and 19 evaluable patients).[128]

Doripenem was not inferior to meropenem in the treatment of lower respiratory infections, according to results of a Japanese trial.[127] In patients with CAP or chronic respiratory disease with acute infections, doripenem was noninferior to meropenem, with a clinical efficacy rate ≥90% (primary efficacy endpoint; table IX). Results in the per-protocol population were supported by mITT analyses (full analysis set), in that clinical efficacy was evident in 88.9% of doripenem (n = 108) and 86.8% of meropenem (n = 106) recipients (between-group difference 2.1%; 95% CI −6.7, 10.9).[127] Bacteriological eradication was seen in 86.0% of doripenem and 95.8% of meropenem recipients. At the post-therapy follow-up visit (n = 99), 11.4% of doripenem and 7.3% of meropenem recipients had evidence of recurrent infection or re-infection.[127] When analysed by diagnosis (CAP or chronic respiratory tract infection), the presence or absence of underlying disease or complicating factors, or previous antibacterial therapy, clinical efficacy rates were ≥89% and did not differ between doripenem or meropenem.[127]

Table IX
figure Tab9

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

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In patients with chronic respiratory tract infection or CAP and other pulmonary infection (n = 102[136] and 41[137]) that were included in two noncomparative trials of mixed infections, doripenem 125 mg twice daily, 250 mg two or three times daily or 500 mg twice daily achieved clinical response rates of 85–95% at treatment end and bacteriological eradication rates of 86–100%.[136,137]

5.1.1 Nosocomial Pneumonia

Doripenem was not inferior to imipenem/cilastin[129] or piperacillin/tazobactam[126] in patients with nosocomial pneumonia, including those with VAP. Clinical cure rates with doripenem at the TOC visit were noninferior to those with either comparator in both the clinically evaluable (table IX) and clinical mITT populations. In the latter analyses, a clinical cure was seen in 59.0% of doripenem and 57.8% of imipenem/cilastin recipients with VAP (between-group difference 1.2%; 95% CI −7.9, 10.3),[129] and 69.5% of doripenem and 64.1% of piperacillin/tazobactam recipients with nosocomial pneumonia (between-group difference 5.4%; 95% CI −4.1, 14.8).[126] Combined clinical cure rates in the microbiologically evaluable population at the TOC visit were 74.5% with doripenem (n = 200) and 70.5% with the comparators (imipenem/cilastin or piperacillin/tazobactam) [n = 193].[130]

Patients receiving doripenem (n = 249) experienced a significantly shorter median hospital length of stay (22 vs 27 days; p = 0.01) and duration of mechanical ventilation (7 vs 10 days; p = 0.03) than imipenem/cilastin recipients (n = 250), although length of stay in the intensive care unit with either treatment did not differ (median of 12 vs 13 days) [clinical mITT analysis].[142]

Subgroup analyses showed that doripenem maintained good efficacy in higher risk patient subgroups. For instance, clinical cure rates were ≥57% with doripenem,[126,129] imipenem/cilastin[129] or piperacillin/tazobactam[126] in patients with nosocomial pneumonia (including VAP) who were elderly (aged ≥65 years)[126,129] or had APACHE II scores >15[126] or >20.[129]

Microbiological cure rates with doripenem, imipenem/cilastin or piperacillin/tazobactam in the microbiologically evaluable population were ≥67% (table IX).[126,129] Pooled results in the microbiologically evaluable population showed that the microbiological cure rate was 78.0% (156 of 200 patients) with doripenem and 73.1% (141 of 193 patients) with imipenem/cilastin or piperacillin/tazobactam and per-pathogen eradication rates with doripenem were ≥74%.[130] Microbiological cure rates by selected bacterial pathogen from the two clinical trials[126,129] are shown in figure 2. In patients with P. aeruginosa, K. pneumoniae or E. coli infections at baseline in the VAP study, microbiological cure rates were numerically higher with doripenem than imipenem/cilastin (figure 2); however, the number of isolates in each comparison were small and between-treatment differences were not statistically significant.[129]

Fig. 2
figure 2

Efficacy of intravenous doripenem (DOR) in patients with ventilator-associated pneumonia (VAP) or nosocomial pneumonia. Microbiological response rates by pathogen in the microbiologically evaluable population in two randomized, open-label, multicentre clinical trials comparing DOR with (a) piperacillin/tazobactam (TZP)[126] and (b) imipenem/cilastin (IPM).[129] Adult patients received 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]), TZP 4.5 g every 6 hours[126] or IMP 500 mg every 6 hours, or 1000 mg every 8 hours[129] for 7–14 days. Where reported,[129] eligible patients had a measurable outcome at the test-of-cure visit and at least one baseline pathogen susceptible (or of intermediate susceptibility) to the study drug. Microbiological cure was usually defined as eradication or presumed eradication.[129] The number of patients in whom the individual pathogens were isolated at baseline are shown above each bar. MSSA = methicillin-susceptible Staphylococcus aureus.

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A clinical cure was achieved in 13 of 14 evaluable patients with nosocomial pneumonia who received doripenem 1–2 g/day as divided doses two or three times daily for 8–13 days in a small Japanese trial.[141]

5.2 Complicated Intra-Abdominal Infection

The efficacy of intravenous doripenem 500 mg three times daily was compared with that of intravenous meropenem 1000 mg three times daily in two randomized, double-blind, double-dummy, noninferiority trials in patients with cIAIs requiring parenteral antibacterial therapy (one fully published[131] and the other[132] reported as an abstract and poster). An analysis of the combined results of these two studies (reported as an abstract and poster)[133] is also available. The duration of study therapy was a minimum of 5 days and a maximum of 14 days; however, patients could be switched to oral amoxicillin/clavulanic acid after at least nine doses of doripenem or meropenem.[132] Randomization was stratified by geographic region, and within each region, by primary site of infection (localized appendicitis vs other sites of IAI) and by severity of illness (APACHE II score ≤10 or >10).[131–133] E. coli was the most frequently isolated pathogen at baseline.[131,132]

The co-primary efficacy endpoints were clinical response at the TOC visit 21–60 days after completing treatment with the study drug (intravenous doripenem or meropenem alone or doripenem or meropenem followed by oral amoxicillin/clavulanic acid therapy) in the microbiologically evaluable population and clinical response in the the microbiological mITT (mMITT) population up to 60 days after the last dose of the study drug.[131,132]

Doripenem was not inferior to meropenem in the treatment of cIAI.[131,132] Clinical cure rates at the TOC assessment were ≥75%, and outcomes with doripenem were noninferior to those with meropenem in both the microbiologically evaluable (table X) and the mMITT (co-primary endpoints) patient populations (77.9% vs 78.9%, between-group difference −1.0% [95% CI −9.7, 7.7] in one study;[131] and 74.5% vs 75.7%, between-group difference −1.2% [95% CI −10.3, 8.0] in the other[132]). The mMITT patient population included 195[131] and 200[132] doripenem recipients and 190[131] and 185[132] meropenem recipients. Doripenem showed good bacterial eradication rates for organisms associated with cIAIs, including Enterobacteriaceae, P. aeruginosa and viridans Streptococci group;[131,132] for instance, eradication rates with doripenem or meropenem for E. coli were 87.5% and 84.0% (between-group difference 3.5%; 95% CI not reported) in one study[131] and 87.5% and 84.8% (between-group difference 2.7; 95% CI −7.6, 13.0) in the other.[132]

Table X
figure Tab10

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]

Full size image

An analysis of combined results from these two trials confirmed the noninferiority of doripenem to meropenem in cIAI.[133] Clinical cure rates in the microbiologically evaluable population at EOT was 84.6% for doripenem (n = 325) and 84.1% for meropenem (n = 309) [between-group difference 0.5%; 95% CI −5.5, 6.4], while those in the mMITT population were 76.2% (n = 395) and 77.3% (n = 375), respectively (between-group difference −1.1%; 95% CI −7.4, 5.1).[133] A microbiological cure was achieved in 84.3% of doripenem and 84.5% of meropenem recipients in the microbiologically evaluable population.[133] Bacterial eradication rates with doripenem or meropenem were 88% and 84% for E. coli, 78% and 95% for K. pneumoniae, 84% and 79% for B. fragilis, and 85% and 75% for P. aeruginosa.[133]

Two small, noncomparative trials (n = 48 and n = 15) in Japanese patients with IAI (including patients with cholecystitis, cholangitis and hepatic abscesses) found that intravenous doripenem 250 mg two or three times daily, or 500 mg twice daily for 3–14 days achieved clinical response rates (assessed as ‘excellent’ or ‘good’ clinical responses) of 90% and 100%, and bacterial eradication rates of 61% and 55%.[107] The most common pathogens isolated at baseline were P. aeruginosa, K. pneumoniae, E. faecalis, E. coli and B. fragilis.[107]

5.3 Complicated Urinary Tract Infection

The efficacy of intravenous doripenem 250 mg twice daily was compared with that of intravenous meropenem 500 mg twice daily in a Japanese randomized, double-blind trial in adult patients with cUTIs requiring parenteral antibacterial therapy.[135] Intravenous doripenem or meropenem was administered for 5 days in this trial.[135] In another trial (in non-Japanese adult patients with cUTIs requiring parenteral antibacterial therapy), doripenem 500 mg three times daily infused over 30–60 minutes was compared with levofloxacin 250 mg once daily (reported as an abstract and poster).[134] This trial was randomized, double-blind and double-dummy in design, and the planned duration of treatment was 10 days.[134] Patients could be switched to oral levofloxacin tablets (250 mg once daily) after a minimum of 3 days intravenous therapy (nine doses of doripenem). The actual treatment duration was a mean 9.5 days in the doripenem arm and 9.1 days in the levofloxacin arm (intent-to-treat analysis). Patients received a mean 5.4 days of intravenous doripenem or 5.3 days of intravenous levofloxacin before switching to oral levofloxacin (mean of ≈6 days’ treatment).[134] A minority of patients received only intravenous therapy (11% of doripenem and 18% of levofloxacin recipients) for the treatment duration.[134]

Inclusion criteria in the Japanese trial were pyuria of at least five white blood cells per high-power field and bacteriuria of ≥104 CFU/mL, and identifiable underlying urinary tract disease.[135] Most patients were male (72% of the per-protocol population [n = 155]) and ≥75% were aged 60–80 years.[135] At baseline, ≈50% of patients were diagnosed with cystitis[135] and ≈50% were diagnosed with pyelonephritis.[135] Renal function was normal in 83% of patients in the Japanese trial.[135] Patients were included in the trial in non-Japanese patients if a clinical and microbiological diagnosis of cUTI (complicated lower UTI [cLUTI], or complicated or uncomplicated pyelonephritis) was made.[134] Most patients were female (61% of 545 microbiologically evaluable patients) and ≈36% of patients were aged ≥65 years.[134] At baseline, ≈50% of patients were diagnosed with cLUTI[134] and ≈50% were diagnosed with pyelonephritis (severe in 9% of patients).[134] Renal function was normal or mildly impaired (CLCR ≥3.0 L/h) in 87% of patients.[134]

E. coli was the most frequent pathogen isolated at baseline in both studies;[134,135] other organisms isolated included E. faecalis, P. aeruginosa, K. pneumoniae, S. epidermidis, S. marcescens and P. mirabilis.

Both trials were noninferiority studies in which the noninferiority of doripenem to the comparator drug was established if the lower limit of the 95% CI for the difference in the rates of microbiological cure[134] or overall clinical efficacy[135] between the two treatment groups was greater than or equal to −10%. The primary efficacy endpoint in the Japanese trial was overall clinical efficacy (classed as ‘excellent’, ‘moderate’ or ‘poor’, according to criteria proposed by the Japanese UTI Committee in the per-protocol patient population). The per-protocol population was defined as patients who met the protocol-specified disease definition of cUTI, who had an interpretable urine culture at baseline and at the efficacy assessment visit, and who had no entry criteria or protocol violation during treatment that was likely to affect the microbiological outcome. Secondary endpoints included bacteriological response, defined as the percentage of bacterial strains eradicated or presumed eradicated.[135]

The co-primary efficacy endpoints in the other trial were microbiological cure rate (eradication of baseline pathogens [<104 CFU/mL]) at the TOC visit (6–11 days after completing study drug therapy) in the microbiologically evaluable and mMITT populations.[134] The microbiologically evaluable population was defined as patients who met the protocol-specified disease definition of cUTI, who had a study-qualifying pre-treatment urine culture (at least one, but no more than two bacterial uropathogens each at ≥105 CFU/mL) and an interpretable urine culture at the TOC visit, and who had no entry criteria or protocol violation during treatment that was likely to affect the microbiological outcome. The mMITT population included all randomized patients who received at least a partial dose of study therapy and had a study-qualifying pre-treatment urine culture.[134] Secondary endpoints included the microbiological cure rate in microbiologically evaluable patients with E. coli infection at baseline, and microbiological cure rate in the clinically evaluable population (patients who met the criteria for the microbiologically evaluable population but were required to have a clinical outcome assessment, rather than an interpretable urine culture, at the TOC visit).[134]

Doripenem was not inferior to meropenem[135] or levofloxacin[134] in two trials in patients with cUTIs. At the TOC visit, clinical response rates with doripenem or meropenem were ≥88% in the per-protocol population in the Japanese trial[135] (primary endpoint; table XI). The bacteriological response rate with doripenem was noninferior to that with meropenem in the Japanese trial (table XI; between-group difference and 95% confidence intervals not reported), as were clinical efficacy rates judged by the attending urologist (93.4% vs 92.4% [between-group difference and 95% confidence intervals not reported]).[135] Bacterial eradication rates with either agent for Gram-negative or Gram-positive pathogens were >95%.[135]

Table XI
figure Tab11

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

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In the trial in non-Japanese patients, microbiological cure rates were ≥78% with doripenem or levofloxacin in the microbiologically evaluable and mMITT populations (co-primary endpoint; table XI).[134] Doripenem was also noninferior to levofloxacin in the group of microbiologically evaluable patients with E. coli isolated at baseline in terms of microbiological eradication rates (84.4% vs 87.2% [between-group difference −2.8; 95% CI −10.0, 4.5]). Microbiological eradication rates with doripenem or levofloxacin were 55% and 29% in patients with levofloxacin-resistant (MIC ≥8 mg/L) E. coli, 83% and 63% in K. pneumoniae infection, and 70% and 87% in P. mirabilis infection.[134] Results in the clinically evaluable population at TOC supported the co-primary efficacy outcomes shown in table XI.[134]

A Japanese dose-finding trial of intravenous doripenem in patients with cUTI found that there was no significant difference in efficacy between doripenem 250 or 500 mg administered twice daily.[138] Overall efficacy was seen in 97.4% of patients in the doripenem 250 mg twice daily group and 96.9% of those in the 500 mg twice daily group (primary endpoint). In addition, there were no significant between-group differences for secondary endpoints, including effect on pyuria or bacteriuria and bacteriological response.[138]

Two noncomparative phase II studies demonstrated the efficacy of intravenous doripenem in patients with cUTI.[137,139] In a study evaluating doripenem 125–500 mg twice daily or 500 mg three times daily administered for 3–15 days in patients with respiratory tract infections or cUTIs, overall efficacy was seen in 94% of patients with cUTIs (n = 32), with a bacterial eradication rate of 97% (n = 34).[137] In the other study,[139] which included 6 patients with acute prostatitis, 5 patients with epididymitis and 21 patients with cUTI, doripenem 250 mg two or three times daily or 500 mg twice daily for 3–14 days achieved 84% clinical efficacy judged by attending urologists (27 of 32 patients), and bacterial eradication was 97% (33 of 34 strains isolated at baseline). When assessed by Japanese UTI committee criteria, overall clinical efficacy for cUTIs (n = 16) was 100%. [139]

5.4 Other Infections

Several small, noncomparative studies in Japanese patients have examined the efficacy of intravenous doripenem in a variety of moderate or serious bacterial infections.[108–112,136,140] In these studies, clinical efficacy refers to percentages of patients with ‘excellent’ or ‘good’,[108–111,136] or ‘cured’ or ‘improved’[112,140] clinical responses.

5.4.1 Skin and Skin Structure Infections

Doripenem 250 or 500 mg twice daily for 5–8 days demonstrated good efficacy in the treatment of a range of deep-seated skin infections in a small, noncomparative, Japanese study.[112] A clinical response (cured or improved) was seen at day 7 in all 19 patients (mean age at entry of 50.5 years). The bacteriological response rate was 85% (17 of the 20 pathogens isolated were eradicated).[112] At study entry, ten patients were diagnosed with cellulitis, three with erysipelas, three with lymphangitis, one with lymphadenitis and two with carbuncles. The most common pathogens isolated at baseline were S. aureus, S. pyogenes and K. oxytoca.[112]

5.4.2 Obstetric and Gynaecological Infection

In a small noncomparative study, doripenem showed efficacy in women with moderate or severe gynaecological infection.[108] Intravenous doripenem 250 mg administered two or three times daily, or 500 mg administered twice daily for 3–14 days (mean of 7.2 days) achieved clinical efficacy (excellent or good response) in 89% of women (n = 54; mean age of 41 years) enrolled in this study. Bacteriological eradication was evident in 80% of microbiologically evaluable patients (24 of 30 patients).[108] Gynaecological infections included in this study were parametritis (18 patients), pelvic peritonitis (14 patients), uterine adnexitis (10 patients), intrauterine infection (9 patients) and pouch of Douglas abscess (3 patients). Infections were severe in 41 patients and moderate in the remaining 13 patients.[108] Pathogens were isolated at baseline in 33 patients, and these included S. aureus, Group B Streptococcus, E. faecium, E. coli, P. aeruginosa and various anaerobes. Two-thirds of patients who were microbiologically evaluable (21 of 30 patients) had polymicrobial infection.[108]

5.4.3 Sepsis and Endocarditis

Intravenous doripenem 500 mg two or three times daily administered for 3–14 days in patients with sepsis (n = 9) and for 28 days in patients with infective endocarditis (n = 2) was associated with clinical cure and eradication of bacterial pathogens in all patients in a small study.[140] Patients were aged 59–79 years and had APACHE II scores ranging from 6 to 16.[140] Sepsis was secondary to urological infection in seven patients and surgery in two patients and, where identified, causative pathogens were E. coli and K. pneumoniae.[140] The causative organisms in patients with infective endocarditis were Streptococcus spp. (S. sanguis and S. vestibularis [MICs not reported]).[140]

5.4.4 Ear, Nose and Throat Infections

In 12 adult patients with moderate to severe otitis media or tonsillitis (including peritonsillar abscess), intravenous doripenem achieved clinical efficacy in 92% of patients (11 of 12 patients) and a bacteriological eradication rate of 92% (11 of 12 organisms).[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 three times daily, or 500 mg twice daily was administered for 6–7 days. The most common pathogens isolated at baseline were S. aureus, S. pyogenes and P. aeruginosa.[109]

In a study of doripenem 250 mg two or three times daily, or 500 mg twice daily for 3–14 days in patients with a range of serious infections (n = 105), clinical efficacy was achieved at treatment end in both of the patients who had peritonsillar abscess.[136]

5.4.5 Dental and Oral Surgical Infection

Intravenous doripenem showed efficacy in a small study in 24 patients with osteitis or cellulitis associated with dental or oral infection.[110] Clinical efficacy at end of treatment was achieved in 100% of patients and bacteriological eradication was evident in 96% of patients (23 of 24 patients).[110] Doripenem 250 mg two or three times daily, or 500 mg twice daily was administered for 3–7 days. Most infections were polymicrobial, and included a mixture of aerobic Gram-positive or Gram-negative bacteria and anaerobes. The most common pathogens isolated at baseline were Streptococcus spp. (S. sanguis, S. mitis, S. oralis and S. constellatus).[110]

5.4.6 Ophthalmic Infection

Doripenem penetrates aqueous humor, evidenced by concentrations of the drug of 0.16–0.87 mg/L within 1–2 hours of starting an infusion of a 250 mg intravenous dose.[111] Consequently, doripenem has been studied in patients with ophthalmic infection. In 15 patients with ophthalmic infection (eight patients had pathogens isolated at baseline), intravenous doripenem achieved a clinical response in 100% of patients and bacteriological eradication of all causative pathogens.[111] Doripenem 250 mg two or three times daily, or 500 mg twice daily was administered for 5–12 days (no local treatment was administered). Ten patients were diagnosed with corneal ulcer; four patients had an orbital infection and one patient had endophthalmitis.[111] The most common organisms isolated at baseline were Corynebacterium spp. (two corneal ulcer and one endophthalmitis patients) and P. aeruginosa (two corneal ulcer patients).[111]

6. Tolerability

Discussion in this section is based on data from the seven randomized, multicentre, comparative clinical studies[126,127,129,131–135] reviewed in section 5, supplemented by data from the Japanese[12] and the US[13] prescribing information.

Doripenem was generally well tolerated in both Japanese and non-Japanese patients in clinical trials,[12,13] and adverse events were mild or moderate in severity.[126,127,129,131,132,134,135] In individual trials, treatment-emergent adverse events (regardless of causality) were reported in 35–83% of doripenem recipients,[127,131,132,134] 27–78%[127,131,132] of meropenem recipients and 60% of levofloxacin recipients.[134] In two trials in patients with cIAIs[131,132] and a trial in patients with cUTIs including pyelonephritis,[134] the most common adverse events occurring in ≥1% of patients who received doripenem, meropenem or levofloxacin, regardless of causality, were headache, nausea, diarrhoea, anaemia, phlebitis and rash (figure 3).[13]

Fig. 3
figure 3

Tolerability of intravenous doripenem (DOR) in adult patients (pts) with complicated urinary tract infections (cUTIs) or complicated intra-abdominal infections (cIAIs). (a) Combined results[13] of two trials[131,132] in which patients with cIAIs received 5–14 days of intravenous DOR 500 mg every 8 hours infused over 60 min (n = 477) or meropenem (MEM) 1 g every 8 hours administered as a bolus over 3–5 min (n = 469) and (b) results[13] of a trial[134] in which patients with cUTIs were treated for a total of 10 days with 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 DOR or at least three doses of LVX) of switching to oral LVX 250 mg once daily for the remainder of the treatment period. Adverse events occurring in ≥1% of patients in any treatment arm, regardless of cause.

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Treatment-related adverse events were uncommon (incidence of 4.4%; 37 of 835 patients) in Japanese doripenem recipients (835 individuals evaluable at the time of approval in Japan),[12] and diarrhoea (0.7%) and rash (0.6%) were the most frequent adverse events reported. The incidence of treatment-related adverse events with doripenem or comparator drugs did not differ significantly in the individual randomized, comparative trials,[126,127,129,133–135] and the most frequent treatment-related adverse events in any treatment arm were gastrointestinal (mainly nausea or diarrhoea), headache and phlebitis.

Severe treatment-related adverse events, such as hypersensitivity reactions or Clostridium difficile colitis, were rare (both at frequency of <1%) in these three trials and few patients discontinued doripenem therapy because of an adverse event (0.2% due to nausea, 0.1% due to vulvomycotic infection and 0.1% due to rash).[13] No treatment-related serious adverse events were reported in the individual randomized trials.[127,131,132,134,135]

Laboratory abnormalities were generally infrequent in clinical trials in non-Japanese patients with cIAI, cUTI or nosocomial pneumonia.[129,131,132,134] For example, in the cIAI and cUTI trials, elevated liver enzymes occurred in 1–2% of doripenem recipients, 3% of ciprofloxacin recipients and 3% of meropenem recipients.[13] Abnormal laboratory results were reported in 23.8% of Japanese individuals (818 evaluable) who had received doripenem up to the time of approval of the drug in Japan.[12] The most frequent abnormalities were increased ALT (12.7%) or AST (9.7%) levels.[12] In the randomized comparisons between doripenem and meropenem in Japanese patients, the incidence and type of treatment-related abnormal laboratory results did not differ between the doripenem and meropenem groups.[127,135]

Seizures were reported in 0–1.3% of doripenem, 0% of meropenem, 0.3% of levofloxacin, 2.7% of piperacillin/tazobactam and 3.8% of imipenem/cilastin recipients in the randomized, comparative trials;[126,127,129,131,132,134,135] however, apart from one incident in an imipenem/cilastin recipient,[129] all were thought to be unrelated to the study medication.[126,129,134] Few patients died in any of these clinical trials, and none of the deaths reported were deemed related to the study medication.[126,127,129,131,132,134,135]

Treatment-emergent anaphylaxis, interstitial pneumonia, Stevens Johnson syndrome, seizure and toxic epidermal necrolysis have been observed with doripenem therapy during postmarketing surveillance, although frequency and causality have not been established.[13] Doripenem is currently contraindicated in patients who have demonstrated anaphylactic reactions to β-lactam agents or who have a known sensitivity to carbapenems.[12,13]

7. Dosage and Administration

Doripenem is indicated in Japan for use as a single agent in the treatment of adult patients with a wide range of infections (see table XII) caused by susceptible strains of Staphylococcus spp., Streptococcus spp., Enterococcus spp. (except E. faecium), M. catarrhalis, E. coli, Citrobacter spp., Klebsiella spp., Enterobacter spp., Serratia spp., Proteus spp., M. morganii, Providencia spp., H. influenzae, P. aeruginosa, Acinetobacter spp., Peptostreptococcus spp., Bacteroides spp. and Prevotella spp.[12]

Table XII
figure Tab12

Approved indications for intravenous doripenem in Japan[12]

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The recommended dosage regimen in Japan is 250 mg two or three times daily (infused over 30–60 minutes), although the dosage can be increased, depending on patient age and symptoms.[12] The maximum individual dose is 500 mg, and the maximum daily dosage is 1.5 g/day.[12]

In the US, doripenem is indicated as a single agent for the treatment of adult patients (aged ≥18 years) with cIAIs or cUTIs, including pyelonephritis, caused by susceptible strains of designated pathogens.[13] For cIAIs, these pathogens are B. caccae, B. fragilis, B. thetaiotaomicron, B. uniformis, B. vulgatus, E. coli, K. pneumoniae, P. micros, P. aeruginosa, S. constellatus and S. intermedius; for cUTIs, including pyelonephritis, they are A. baumannii, E. coli (including patients with concurrent bacteraemia), K. pneumoniae, P. mirabilis and P. aeruginosa.[13]

The recommended dosage regimen for doripenem in the US is 500 mg every 8 hours (infused over 60 minutes) for 5–14 days (patients with cIAIs) or 10 days (patients with cUTIs, including pyelonephritis).[13] In patients with cUTIs, including pyelonephritis, and concurrent bacteraemia, doripenem can be administered for up to 14 days.[13] Patients may be switched to an orally administered antibacterial agent after 3 days of doripenem therapy upon the demonstration of clinical improvement.[13]

Doripenem is approved in the EU for use in adult patients with nosocomial pneumonia (including VAP), cIAIs and cUTIs.[14] The recommended dosage in the EU is 500 mg every 8 hours, for 5–14 days, infused over 1 hour in patients with cIAIs or cUTIs (including pyelonephritis) and over 1 or 4 hours in patients with nosocomial pneumonia (including VAP).[14]

Doripenem is formulated as a powder for reconstitution with 100 mL of physiological saline (sodium chloride 0.9%) in Japan,[12] or with sterile water or sodium chloride 0.9% to produce a suspension containing 500 mg in 10 mL then diluted with 100 mL of sodium chloride 0.9% or dextrose 5% in the US and EU.[13,14] At a controlled room temperature, doripenem solution is stable for up to 4 hours when reconstituted with dextrose and up to 12 hours when reconstituted with physiological saline. At a refrigerated temperature of 2–8°C protected from light, the drug is stable for up to 24 hours in a dextrose solution and up to 72 hours in physiological saline.[14]

Dosage adjustment is recommended for patients with renal impairment.[12–14] Doripenem is not recommended in patients aged <18 years because of a lack of efficacy and tolerability data.[12–14]

The local manufacturer’s prescribing information should be consulted for other contraindications, drug interactions, monitoring requirements, precautions, details of dosage adjustments in renal impairment and use in other special patient populations.

8. Place of Doripenem in the Management of Bacterial Infections

Prompt and appropriate use of antimicrobial therapy, including using local microbiological data in selecting appropriate treatment,[143–145] is important in reducing morbidity and mortality associated with serious bacterial infections.[2,144,146]

Among the antibacterial agents commonly used in this setting are the carbapenems, a class of broad-spectrum β-lactam antibacterials identified in the 1970s.[1] In addition, panipenem/betamipron[11] (approved in Japan, China and Korea) and biapenem[10] (approved in Japan) have been available for several years.[1] Doripenem was approved in Japan in 2005 for use in a wide range of serious infections due to Gram-negative, Gram-positive or anaerobic pathogens,[12] in the US in late 2007 for use in adult patients with cIAIs or cUTIs,[13] and in the EU in 2008 in adult patients with nosocomial pneumonia (including VAP), cIAIs and cUTIs.[14] Doripenem is currently undergoing pre-approval review for use in nosocomial pneumonia, including VAP, in the US[147] and for use in adult patients with cIAIs, cUTIs or nosocomial pneumonia, including VAP, in other countries worldwide.[147]

Imipenem/cilastin or meropenem are well established, appropriate choices for the empirical treatment of serious bacterial infections in a hospital setting, including nosocomial infections, because of their broad spectrum of antibacterial activity and good efficacy.[1,144] Meropenem is administered every 8 hours as a 500 mg dose infused over 15–30 minutes (skin and skin structure infections), or a 1000 mg dose administered as a 15- to 30-minute infusion or as an intravenous bolus injection (in cIAIs),[148] while imipenem/cilastin is usually administered every 6 or 8 hours as a 500 mg dose infused over 40–60 minutes (in moderate or severe infections with susceptible organisms).[149] In general, imipenem has slightly greater activity against Gram-positive organisms than meropenem, while meropenem is slightly more active than imipenem against Gram-negative organisms.[1] Nevertheless, both have broad-spectrum activity, including against non-fermenting Gram-negative bacteria. Doripenem, although more recently approved, is considered a viable alternative to these agents because of its similar spectrum of activity and clinical efficacy to imipenem against Gram-positive organisms and to meropenem against Gram-negative organisms,[144] and good activity against P. aeruginosa and other non-fermentative Gram-negative bacilli.[1,68] Importantly, doripenem activity against Gram-negative pathogens is generally 2- to 4-fold greater than that of imipenem (section 2.2.1).[144] Doripenem is usually administered every 8 hours as a 250 mg (in Japan only) or 500 mg dose infused over 30–60 minutes,[12,13] although more aggressive administration scheduled may be required in critically ill patients with altered pharmacokinetics (e.g. with increased Vd).[144] In contrast, ertapenem is not suited for empirical use in nosocomial infections because of an absence of activity against non-fermentative Gram-negative pathogens.[8] Doripenem (like meropenem,[5–7,150] ertapenem[8,9] or biapenem,[10] but unlike imipenem[4] or panipenem[11]) is stable to the human renal enzyme DHP-1 (section 2.1) and does not need to be coadministered with a DHP-1 inhibitor to achieve clinical efficacy (e.g. cilastin plus imipenem[4]) or to reduce nephrotoxic potential (e.g. betamipron plus panipenem[11]). Doripenem is also resistant to inactivation by most β-lactamases, including ESBLs (section 2).

Like meropenem[150] or imipenem,[4] doripenem has a short t½β (section 3); consequently, doripenem requires administration two or three times daily, usually as a 30- to 60-minute infusion (section 7). Unlike the other available carbapenems,[144] doripenem is stable at room temperature for up to 12 hours when reconstituted with normal saline (section 7), which means that it may have potential for prolonged infusion regimens (e.g. the 4-hour infusion used in a clinical trial[129] in VAP [section 5.1.1]), thus achieving the T > MICfree targets required in more difficult-to-treat nosocomial infections.[143]

Plasma concentrations of doripenem are estimated to achieve an optimal bactericidal pharmacodynamic target attainment against most pathogens associated with serious bacterial infections, including nosocomial pneumonia, cUTI or cIAI (section 4). The drug has shown good penetration into a wide range of tissues, including lung, intra-abdominal, and head and neck tissues, and peritoneal fluid, and demonstrates low serum protein binding (section 3).

Doripenem demonstrated in vitro activity against a wide range of Gram-negative, Gram-positive and anaerobic organisms associated with serious or nosocomially acquired infections (section 2.2), and has rapid, time-dependent bactericidal activity against clinically important Gram-negative and Gram-positive pathogens (including P. aeruginosa, E. coli and S. aureus) and various anaerobes. In addition, doripenem has an in vitro PAE of ≈2 hours against P. aeruginosa and S. aureus (section 2.2.5). This broad spectrum of activity means that doripenem is suitable for use as an empirical treatment for serious bacterial infections, such as serious lower respiratory infections (including nosocomial pneumonia, VAP or severe CAP), cIAI, cUTIs, gynaecological and obstetric infections and sepsis, especially as these conditions are often polymicrobial, including mixed aerobic/anaerobic, infections. Like meropenem[150] or biapenem,[10] doripenem had a low propensity for inducing seizures in animal studies (section 2.5) and was not associated with seizures in clinical trials (section 6).[44] However, further investigation in a clinical setting is required to confirm these results.

Numerous randomized, phase III clinical trials have shown doripenem to be an effective and well tolerated treatment in a wide range of serious bacterial infections (section 5). Doripenem was as effective as comparator antibacterials, including meropenem in complicated lower respiratory infections, cIAIs and cUTIs, imipenem/cilastin or piperacillin/tazobactam in nosocomial pneumonia (including VAP) and levofloxacin in cUTIs (section 5.1, section 5.2 and section 5.3). Doripenem also demonstrated efficacy in a range of other infections, including cSSSI, obstetric or gynaecological infections, sepsis and endocarditis, severe ENT, dental or oral surgical infections and severe ophthalmic infections (section 5.4).

Pharmacoeconomic analyses of doripenem, including analyses based on efficacy and hospital resource utilization data discussed in section 5, would be useful in determining the cost effectiveness of the drug, relative to other carbapenems or conventional combination antibacterial treatments in patients with serious bacterial infections.

International treatment guidelines[151–157] support the use of carbapenems, such as imipenem/cilastin or meropenem, as an option in the initial treatment of nosocomial pneumonia and/or severe CAP (in combination with ciprofloxacin where there is a risk of P. aeruginosa),[153–155] cUTIs,[156] incisional surgical site infection after intestinal or genital tract surgery,[151] and severe IAIs,[152] and list carbapenems in a range of first-line regimens in the treatment of polymicrobial necrotizing infections of the skin, fascia and muscle, or as intravenous options in infections after a human or an animal bite.[151] These guidelines were published prior to the approval of doripenem outside of Japan, and thus do not include doripenem among the carbapenems recommended. Japanese guidelines[158,159] support the use of doripenem, meropenem or imipenem/cilastin as a second-line option in the treatment of moderate or severe cholangitis[158] and use of carbapenems in severe pneumococcal pneumonia requiring inpatient treatment or as empirical therapy in combination with new quinolones, tetracyclines or macrolides in patients with severe CAP who require admission to the intensive care unit.[159]

Increased and/or inappropriate use of broad-spectrum antibacterial agents, such as the third-generation cephalosporins, in serious bacterial infections has resulted in a global increase in resistant bacterial strains, including ESBL- and AmpC-producing Enterobacteriaceae, and multidrug-resistant P. aeruginosa.[2,146,160] Because of their broad spectrum of activity, carbapenems are considered first-line options in the empirical treatment of serious infections that may be associated with ESBL-producing Enterobacteriaceae or P. aeruginosa.[160] Importantly, doripenem retains activity against ESBL- and AmpC-producing Enterobacteriaceae, with little or no increase in MIC90 values when compared with wild-type isolates, has no inoculum effect (section 2.2 and section 2.3) and a low propensity to select for resistance (section 2.3).

Antimicrobial resistance to the non-fermentative Gram-negative pathogens Acinetobacter spp. and P. aeruginosa is increasing worldwide, and multidrug-resistant isolates of P. aeruginosa and A. baumanii are often associated with nosocomial infection.[161–164] Doripenem showed in vitro activity against ceftazidime- or imipenem-susceptible, or non-multidrug-resistant P. aeruginosa isolates in all geographic regions, evidenced by MIC90 values of 0.2–12.5 mg/L and, in some studies, susceptibility rates of 100% (section 2.2). Nevertheless, like other carbapenems, doripenem activity against resistant P. aeruginosa isolates was more limited, with susceptibility rates of ≤40% and MIC90 values of 8–64 mg/L (section 2.2). Doripenem activity against A. baumanii (including ceftazidime intermediate/resistant isolates) was limited in Europe and the Americas, with a susceptibility rate of 76–78% and MIC90 values of 1–32 mg/L; however, lower MIC90 values for Acinetobacter spp. were reported in Japan (0.78–3.13 mg/L) [section 2.2]. As a consequence of its broad spectrum of in vitro activity against Gram-negative bacteria, including those pathogens resistant to other antibacterials, doripenem has potential as a new option in the empirical treatment of patients with severe nosocomial infections, including in settings where there are increased rates of multidrug-resistant Gram-negative bacteria.[144,165]

Of interest, penicillin- or macrolide-resistant S. pneumoniae isolates are more common in Asia (including Japan) than in Western countries. [166] In Japan, >50% of macrolide-resistant isolates are erm B-positive, which is usually associated with higher MICs than mef A-positive isolates.[159] Doripenem showed good in vitro activity against S. pneumoniae, including ceftriaxone-resistant, penicillin-intermediate or -resistant or multidrug-resistant isolates (sections 2.2 and 2.3).

Methicillin or oxacillin-resistant S. aureus, E. faecium and S. maltophilia (section 2.2) are inherently resistant to doripenem and other currently available carbapenems.[1] Although the prevalence of acquired metallo-β-lactamases and carbapenemases is increasing (section 2.3),[78,88] carbapenem resistance remains uncommon and Enterobacteriaceae resistance to carbapenems is rare (section 2.3).[47,160] However, it is important that doripenem (and other carbapenems) are used appropriately as empirical treatment to limit the likelihood of increasing future resistance.[2] Ideally, doripenem should only be used in a hospital setting in severe infections for the shortest possible duration.

As mentioned in section 4, the pharmacodynamic/pharmacokinetic parameter that best correlates with carbapenem bactericidal activity (and therefore efficacy) is T > MICfree, and a T > MICfree of 30–40% is adequate for carbapenem efficacy. Of interest, in animal model of infections, increasing the doripenem dose administration frequency or lengthening the infusion duration was associated with a prolonged T > MICfree and enhanced bactericidal activity, compared with increasing the dose per administration (section 4). This is particularly important when considering pathogens with increased MICs, including P. aeruginosa. Unlike meropenem[148] or imipenem[149] (which maintain potency for only 2[148] or 4[149] hours at room temperature once reconstituted), doripenem solution is stable for up to 12 hours at a controlled room temperature when reconstituted with physiological saline (section 7). Consequently, doripenem is suitable for prolonged infusion regimens, such as the 4-hour infusion used in a trial in patients with VAP[129] (section 5.1.1).

In conclusion, doripenem has a broad spectrum of in vitro activity against Gram-positive and Gram-negative pathogens, including ESBL- and AmpC-producing Enterobacteriaceae, and anaerobic bacteria. 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. Doripenem is at least as effective as other antibacterial agents, including meropenem, imipenem/cilastin, piperacillin/tazobactam or levofloxacin, in the treatment of a variety of serious bacterial infections (e.g. 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 hospitalized patients with serious bacterial infections.

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.