Penicillin-binding proteins (PBPs) [1,2]
Doripenem is a carbapenem antibiotic that inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), including PBP2 and PBP3 in Pseudomonas aeruginosa and PBP1 in Staphylococcus aureus.

In vitro activity: Doripenem is active against Aeromonas (MIC50, 0.03 mg/L), Bacillus spp. (MIC50, 0.03 mg/L) and all tested anaerobic species (MIC range, < or =0.015-4 mg/L), but is less active against S. maltophilia (MIC90, >32 mg/L) and Enterococcus faecium (MIC90, >32 mg/L) among the enterococcal species. Doripenem is the most active carbapenem (MIC90, 1 to 4 mg/mL) against penicillin-resistant streptococci. Doripenem is found to be highly active against oxacillin-susceptible Staphylococcus aureus and coagulase-negative staphylococci (2705 and 297 isolates, respectively; MIC90s 0.06 mg/L), with a potency greater than that of other carbapenem antibiotics. Doripenem is among the most potent agents tested against Streptococcus pneumoniae, viridans group streptococci and beta-haemolytic streptococci (885, 140 and 397 isolates; MIC(90)s 0.5, 0.5 and 0.03 mg/L, respectively). Doripenem is also active against Citrobacter spp., Enterobacter spp. and Serratia spp. (MIC90s 0.06-0.25 mg/L), including ceftazidime-resistant isolates. Doripenem is slightly more potent (MIC50 2 mg/L) than ertapenem and imipenem (MIC50 4 mg/L), and has a potency similar to that of meropenem (MIC50 2 mg/L), against Burkholderia cepacia (20 isolates). Doripenem demonstrates in vitro activity similar to that of meropenem against gram-negative pathogens and to that of imipenem against gram-positive pathogens.

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Cell Assay: Doripenem hydrate was potent against Staphylococcus aureus and Staphylococcus epidermidis with the same MIC90 value of 0.063 µg/ml. Doripenem hydrate was 2-4 times more active than other tested carbapenems against S. aureus. The activity of doripenem hydrate against S. pneumoniae was similar to that of imipenem but higher than that of other tested agents. Doripenem hydrate was potent against S. pneumonia with an activity similar to that of other tested carbapenems (MIC90, 0.5 µg/ml). Doripenem hydrate had an activity similar to that of cefpirome against S. pneumoniae and S. pyogenes. Doripenem hydrate was more active against Enterococcus faecalis than other tested agents except for imipenem.

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- Broad-Spectrum Activity: Doripenem demonstrated potent activity against Gram-negative bacteria, including Pseudomonas aeruginosa and Enterobacteriaceae, with MIC90 values of ≤2 μg/mL for most strains. It also showed activity against Gram-positive pathogens like Staphylococcus aureus [1,2]
- β-Lactamase Stability: Resistant to hydrolysis by most β-lactamases, including extended-spectrum β-lactamases (ESBLs) and AmpC enzymes, due to its carbapenem ring structure [1,2]

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Against 367 clinical anaerobic isolates, Doripenem exhibited potent activity: MIC₉₀ values were 0.5 μg/mL for Bacteroides fragilis, 0.25 μg/mL for Prevotella spp., 0.12 μg/mL for Fusobacterium spp., and 0.25 μg/mL for Clostridium perfringens. Its activity surpassed cefotetan and piperacillin-tazobactam against β-lactamase-producing B. fragilis.
For Gram-positive pathogens, Doripenem showed superior efficacy against oxacillin-susceptible S. aureus and coagulase-negative staphylococci (MIC₉₀ ≤ 0.06 μg/mL), outperforming other carbapenems. It was highly active against Streptococcus pneumoniae, viridans group streptococci, and β-hemolytic streptococci (MIC₉₀: 0.5, 0.5, and 0.03 μg/mL, respectively).
Against Gram-negative pathogens, Doripenem inhibited ESBL-producing Enterobacteriaceae (MIC ≤ 0.5 μg/mL for 90% of strains), Citrobacter spp., Enterobacter spp., and Serratia spp. (MIC₉₀: 0.06–0.25 μg/mL), including ceftazidime-resistant isolates. It was more potent than imipenem (MIC₅₀: 2 μg/mL vs. 4 μg/mL) against Burkholderia cepacia and comparable to meropenem against Aeromonas spp. (MIC₅₀: 0.03 μg/mL).
Doripenem significantly inhibited P. aeruginosa biofilms, with MIC₅₀ and MBIC₅₀ (minimal biofilm inhibitory concentration) values of 0.5 μg/mL and 2 μg/mL, respectively. It reduced biofilm formation, bacterial adhesion, motility, and cell surface hydrophobicity at sub-MIC concentrations. [1]

In mice experimentally induced with acute bacteremia, the ED50 of doripenem hydrate against S. aureus Smith was 0.066 mg/kg. Doripenem hydrate was more effective than other tested carbapenems against S. aureus TUH1. Doripenem hydrate was more effective than other tested agents except for meropenem-cilastatin against E. coli C-11. Doripenem hydrate almost shared the same effectiveness with other tested carbapenems against P. aeruginosa E7. Against P. aeruginosa TUH302, doripenem hydrate was the most effective among tested drugs.

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- Efficacy in Murine Models: In a murine thigh infection model, doripenem administered intravenously at 10 mg/kg reduced bacterial load by >3 log10 CFU compared to untreated controls. Similar efficacy was observed in a rat model of peritoneal sepsis [2]
- Pharmacokinetic Profile: In healthy volunteers, doripenem exhibited a plasma half-life of 1.18 hours after intravenous administration, with 70-80% renal excretion as unchanged drug [2]

PBPs Binding Assay:
1. Membrane fractions from E. coli or P. aeruginosa were incubated with doripenem (0.01–10 μM) in Tris-HCl buffer (pH 7.5) at 37°C for 20 minutes.
2. Binding was detected via radiolabeled [³H]benzylpenicillin displacement, followed by SDS-PAGE and autoradiography.
3. Doripenem showed high affinity for PBP-2 and PBP-3, with IC50 values of 0.05 μM and 0.12 μM, respectively [2]

Bacterial Growth Inhibition:
1. P. aeruginosa strains (10⁶ CFU/mL) were exposed to doripenem (0.06–256 mg/L) in Mueller-Hinton broth.
2. MIC endpoints were determined after 24-hour incubation at 37°C.
3. Doripenem inhibited 90% of strains at ≤2 mg/L [1]

Murine Peritonitis Model:
1. ICR mice were infected intraperitoneally with E. coli (10⁹ CFU).
2. Doripenem (10–100 mg/kg) was administered intravenously every 8 hours for 3 days.
3. Survival rates were monitored for 7 days, with 100% survival at doses ≥50 mg/kg [2]

Absorption, Distribution and Excretion
Doripenum is administered via intravenous infusion. In subjects with normal renal function, no accumulation of doripenum was observed after intravenous infusion of 500 mg or 1 g every 8 hours for 7–10 days. Doripenum is primarily excreted unchanged via the kidneys, mainly through glomerular filtration and active tubular secretion. In healthy adults, mean 71% and 15% of the dose were recovered in urine within 48 hours after a 500 mg dose, respectively, with the unchanged drug and its open-ring metabolites being the open-ring metabolites. In healthy adults, less than 1% of the total radioactivity was recovered in feces one week after a single 500 mg dose of radiolabeled doripenum. The mean volume of distribution (Vd) at steady state in healthy subjects was 16.8 L (8.09–55.5 L). Doripenum can penetrate a variety of tissues and fluids, including potential sites of infection for its approved indications.
10.3 L/h.

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Metabolism/Metabolite
Doribenam is metabolized by dehydropeptidase-1 (also known as dipeptidase-1) to doribenam-M1, a microbially inactive open-ring metabolite. Doribenam does not appear to be a substrate of hepatic CYP450 enzymes.

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Biological half-life
In healthy, non-aged adults, it is 1 hour.

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- Plasma half-life: 1.18 hours in humans after intravenous infusion [2] - Renal excretion: Approximately 70-80% of the dose is excreted unchanged in the urine [2] - Protein binding: 8% in human plasma [2]

Hepatotoxicity
In patients receiving parenteral doribene for 5 to 14 days, 1% to 5% may experience mild, transient, asymptomatic elevations in serum transaminase levels. These abnormalities are usually self-limiting and asymptomatic, rarely exceeding 5 times the upper limit of normal. No cases of hepatitis with jaundice have been reported during the limited time doribene has been marketed. However, cholestatic jaundice has been reported during or shortly after treatment with other carbapenems. The incubation period is 1 to 3 weeks, and the pattern of enzyme elevation is usually cholestatic. Immune allergic reactions may occur, but autoantibodies are rare. The course is usually self-limiting, but at least one case of bile duct disappearance syndrome associated with carbapenems has been reported. Doribene and other carbapenems have not been found to be associated with cases of acute liver failure. Probability score: E (Unproven but suspected cause of liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the clinical use of doribenum during lactation. Its excretion in breast milk is likely similar to that of imipenem and meropenem, which have lower concentrations in breast milk and are not expected to have adverse effects on breastfed infants. There have been reports that β-lactam antibiotics occasionally disrupt the gut microbiota of infants, leading to diarrhea or thrush, but these effects have not been adequately assessed. Doribenum can be used in breastfeeding women.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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- Central nervous system effects: In preclinical studies, doribenum induced seizures in rats at doses ≥200 mg/kg, likely due to its competitive binding to GABA receptors[2]. - Renal safety: No significant nephrotoxicity was observed at therapeutic doses in animal studies [2]. The oral LD₅₀ of doripenem in rats exceeds 5,000 mg/kg, indicating low acute toxicity. In animal models, doripenem showed lower epileptogenicity compared to imipenem. [1]

[1]. J Antimicrob Chemother.2004 Jul;54(1):144-54;
[2]. Antimicrob Agents Chemother.2004 Aug;48(8):3136-40.

Mechanism of action: Doripenum irreversibly inhibits penicillin-binding proteins (PBPs), disrupting peptidoglycan cross-links and leading to bacterial cell lysis [1,2]
- Clinical indications: Approved for the treatment of complicated intra-abdominal infections, urinary tract infections, and pneumonia caused by susceptible pathogens [1,2]
- Limitations: Lower activity against Enterococcus faecalis and Streptococcus pneumoniae compared to other carbapenems [1,2]

Mechanism: Doripenum binds to PBPs with high affinity and remains stable against most β-lactamases, including ESBLs and AmpC enzymes, thereby restoring activity against multidrug-resistant strains.
Antibacterial spectrum: Broad-spectrum antibacterial activity against Gram-positive/negative aerobic and anaerobic bacteria, but ineffective against Pseudomonas aeruginosa (MIC₉₀ > 32 μg/mL) and Enterococcus faecalis (MIC₉₀ > 32 μg/mL).
Stability: Unlike other carbapenem antibiotics, doripenem can be stably stored at room temperature for 12 hours and can be infused for up to 4 hours to maintain drug concentrations above the MIC, thus effectively combating pathogens with low susceptibility.
Indications: Approved for the treatment of complicated intra-abdominal infections (cIAI), urinary tract infections (cUTI), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP) caused by susceptible bacteria. [1]

Doripenem hydrate belongs to the carbapenem antibiotics.

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Drug Indications
Treatment of bacterial infections

C15H24N4O6S2.H2O

438.52

438.124

C, 41.09; H, 5.98; N, 12.78; O, 25.54; S, 14.62

364622-82-2

Doripenem;148016-81-3

636377

Light yellow to yellow solid powder

694.8ºC at 760 mmHg

374ºC

0.771

6

11

7

28

780

6

C[C@@H]1[C@@H]2[C@H](C(=O)N2C(=C1S[C@H]3C[C@H](NC3)CNS(=O)(=O)N)C(=O)O)[C@@H](C)O.O

NTUBEBXBDGKBTJ-WGLOMNHJSA-N

InChI=1S/C15H24N4O6S2.H2O/c1-6-11-10(7(2)20)14(21)19(11)12(15(22)23)13(6)26-9-3-8(17-5-9)4-18-27(16,24)25;/h6-11,17-18,20H,3-5H2,1-2H3,(H,22,23)(H2,16,24,25);1H2/t6-,7-,8+,9+,10-,11-;/m1./s1

(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[(3S,5S)-5-[(sulfamoylamino)methyl]pyrrolidin-3-yl]sulfanyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid;hydrate

S-4661;S 4661; Doripenem hydrate; 364622-82-2; Doripenem monohydrate; Dripenem hydrate; Doripenem hydrate [JAN]; 4B035T6NKT; Doripenem hydrate (JP17); DORIPENEM HYDRATE [MI]; S4661; Doripenem Monohydrate; DRPM; Finibax; Doribax

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 3 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3 mg/mL (6.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 33.33 mg/mL (76.01 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)