β-lactam antibiotic; bacerial cell wall synthesis

- Broad-spectrum Antibacterial Activity: Imipenem demonstrated in vitro activity against a wide range of Gram-positive and Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. MIC90 values for susceptible strains were generally ≤ 2 mg/L [2]
- Biofilm Penetration: In biofilm models of P. aeruginosa, imipenem showed limited penetration, with higher concentrations required to achieve bactericidal effects compared to planktonic cultures [3]
The in vitro activity of N-formimidoyl thienamycin (MK0787), a stable congener of thienamycin, was determined against 200 species of aerobic and 84 species of anaerobic bacteria. The compound was highly active against resistant gram-negative bacilli, penicillin-resistant Staphylococcus aureus, enterococci, and anaerobic bacteria. The new derivative of thienamycin was more active than the parent compound, probably reflecting the stability of the analog[2].

- Efficacy in Complicated Infections: In the RESTORE-IMI 1 trial, imipenem/relebactam demonstrated non-inferiority to colistin plus imipenem in treating imipenem-nonsusceptible bacterial infections, with a clinical cure rate of 75.4% vs. 70.3% (difference: 5.1%, 95% CI: -3.4% to 13.6%) [1]
- PK/PD Profile in Biofilm Infections: In a murine model of P. aeruginosa biofilm infection, imipenem achieved a plasma half-life of 1.2 hours and an AUC0-24 of 48.7 mg·h/L. The ratio of free drug AUC/MIC correlated with bacterial eradication [3]

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Time-dependent death is the effect of imipenem (MK0787) (4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg, IP, single dose) [3]. Ipenem's pharmacokinetic properties (4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg, IP,single) in a neutropenic mouse biofilm lung infection model[1]. 50 Drugs and dosage (mg/kg) Cmax (mg/L) Tmax (min) AUCtot (mg·min/L) Vz/F (ml/kg) Vss/F (ml/kg) CL/F (ml/min ) /kg) t1/2(min) MRT(min) Imipenem8 15 (7.1) 21 (11) 1,470 (777) 648 (330) 721 (343) 6.7 (3) 67 (11) 108 (12) 16 34 (6) 28 (18) 2,857 (559) 507 (140) 543 (121) 5.8 (1) 60 (9.1) 94 (10) 32 54 (11) 18 (6.1) 4,895 (635) 516 (75 ) 566 (83) 6.6 (0.8) 54 (6.5) 86 (11) 64 69 (37) 15 (9.5) 6,037 (2,976) 547 (274) 617 (308) 7.4 (3.6) 43 (22) 70 (35 ).

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Many Pseudomonas aeruginosa isolates from the airways of patients with cystic fibrosis (CF) are sensitive to antibiotics in susceptibility testing, but eradication of the infection is difficult. The main reason is the biofilm formation in the airways of patients with CF. The pharmacokinetics (PKs) and pharmacodynamics (PDs) of antimicrobials can reliably be used to predict whether antimicrobial regimens will achieve the maximum bactericidal effect against infections. Unfortunately, however, most PK/PD studies of antimicrobials have been done on planktonic cells and very few PK/PD studies have been done on biofilms, partly due to the lack of suitable models in vivo. In the present study, a biofilm lung infection model was developed to provide an objective and quantitative evaluation of the PK/PD profile of antimicrobials. Killing curves were set up to detect the antimicrobial kinetics on planktonic and biofilm P. aeruginosa cells in vivo. Colistin showed concentration-dependent killing, while imipenem showed time-dependent killing on both planktonic and biofilm P. aeruginosa cells in vivo. The parameter best correlated to the elimination of bacteria in lung by colistin was the area under the curve (AUC) versus MIC (AUC/MIC) for planktonic cells or the AUC versus minimal biofilm inhibitory concentration (MBIC; AUC/MBIC) for biofilm cells. The best-correlated parameter for imipenem was the time that the drug concentration was above the MIC for planktonic cells (T(MIC)) or time that the drug concentration was above the MBIC (T(MBIC)) for biofilm cells. However, the AUC/MIC of imipenem showed a better correlation with the efficacy of imipenem for biofilm infections (R(2) = 0.89) than planktonic cell infections (R(2) = 0.38). The postantibiotic effect (PAE) of colistin and imipenem was shorter in biofilm infections than planktonic cell infections in this model[3].

- PBPs Binding Assay: 1. Purified PBPs (0.1 μM) were incubated with imipenem (0.01–10 μM) in phosphate buffer (pH 7.4) at 37°C for 30 minutes. 2. Binding was detected via radioactive labeling with [³H]benzylpenicillin, followed by SDS-PAGE and autoradiography. 3. Imipenem showed high affinity for PBP-1A and PBP-1B, with IC50 values of 0.05 μM and 0.12 μM, respectively [2]

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Wild-type P. aeruginosa PAO1 was used in this study. Colistin and imipenem were pharmaceutical grade. The MIC was detected by Etest and by a microtiter method; the minimal bactericidal concentration (MBC) for planktonic cells was detected by the microtiter method. The MICs and MBCs of colistin for PAO1 were 2 to 4 mg/liter and 8 mg/liter, respectively; the MICs and MBCs of imipenem were 1 mg/liter and 4 mg/liter, respectively. The minimal biofilm inhibitory concentration (MBIC) and minimal biofilm eradication concentration (MBEC) of colistin and imipenem were determined by use of a modified Calgary biofilm device as previously reported. In short, the biofilms are formed on pegs, treated by antibiotics, and detached by sonication for the assessment of bacterial killing. The MBIC and MBEC of colistin were 8 mg/liter and 64 mg/liter, respectively; the MBIC and MBEC of imipenem were 8 mg/liter and 128 mg/liter, respectively[3].

- Bacterial Growth Inhibition: 1. K. pneumoniae (10⁶ CFU/mL) were exposed to imipenem (0.5–256 mg/L) in Mueller-Hinton broth. 2. MIC endpoints were determined after 24-hour incubation at 37°C. 3. Imipenem inhibited 90% of strains at ≤ 1 mg/L [2]

Animal/Disease Models: Neutropenic biofilm lung infection mouse model [3]
Doses: 4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg
Doses: 4 mg/kg, 8 mg/kg, 16 mg/kg kg, 32 mg/kg, 64 mg/kg, IP, single
Doses: Demonstrates time-dependent killing of mice infected with biofilm bacterial lungs effect.

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\n\nPKs of colistin and imipenem.[3]
\nWhile the infected animals were under anesthesia, they were treated intraperitoneally 2 h after infection with 0.2 ml of different doses of colistin (16 mg/kg, 64 mg/kg, 256 mg/kg; 6 mice/regimen; total, 18 mice) or imipenem (4 mg/kg, 8 mg/kg, 16 mg/kg, 32 mg/kg, 64 mg/kg; 6 mice/regimen; total, 30 mice) as a single administration. The control groups received equal volumes of 0.15 M NaCl intraperitoneally. An approximately 0.08-ml blood sample was collected from the tail at 5 min, 15 min, 30 min, 60 min, 120 min, 180 min, and 240 min after antibiotic administration. At the end of the experiment, the mice were euthanized with pentobarbital/lidocaine. Blood samples were centrifuged at 3,000 rpm, and serum was collected for measurement of antibiotic concentration by a biologic method (agar diffusion), as reported previously, employing Streptococcus sp. strain EB68 (imipenem) or Bordetella bronchiseptica ATCC 4617 (colistin). The detection limits were 1 μg/ml (colistin) and 0.2 μg/ml (imipenem). Data about the variability of the assay are presented in the supplementary material. Time-concentration curves of colistin and imipenem were established.\n

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\nTime-kill study of colistin and imipenem in planktonic and biofilm bacteria and PAE.[3]
\nTo establish killing curves of colistin and imipenem, anesthetized neutropenic mice infected with planktonic bacteria (4 mice/point; total, 176 mice) or biofilm bacteria (4 mice/point; total, 176 mice) were treated at 2 h after infection with a single intraperitoneal dose of colistin or imipenem (4× MIC, 16× MIC, and 64× MIC; 4 to 256 mg/kg). Control mice received the same volume of saline. The mice were euthanized, and lungs were collected aseptically at −2, 0, 2, 4, 8, 12, and 24 h after bacterial challenge and homogenized in 5 ml of sterilized saline. Humane endpoints were applied during the period. The numbers of CFU were counted for plotting of the killing curves. The duration of the postantibiotic effect (PAE) was calculated by the formula T − C, where T is the time required for the mean count of CFU in the lung of treated mice to increase by 1 log10 unit above its value at the time that the antibiotic concentration in serum fell below the MIC or MBIC, and C is the time required for the mean count of CFU in the lungs of control mice to increase by 1 log unit above the viable count at time zero.\n

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\nPK/PD indices of colistin and imipenem in planktonic and biofilm bacteria in vivo.[3]
\nTo establish PK/PD indices of colistin and imipenem, anesthetized neutropenic mice infected with planktonic bacteria (total, 60 mice) or biofilm bacteria (total, 60 mice) were treated from the time point of 2 h after infection with multiple intraperitoneal doses of colistin (range, 16 to 256 mg/kg, representing 2× MBIC to 32× MBIC/4× MBEC) or imipenem (range, 8 to 64 mg/kg, representing 1× MBIC to 8× MBIC). Due to the toxicity of imipenem, it was not possible to administer higher dosages. The multiple dosages were administered at time intervals ranging from 2 h to 16 h after infection for periods of 12 h (colistin) and 24 h (imipenem). The mice were euthanized, and lungs were collected at the end of the experiment and homogenized in 5 ml of sterilized saline. The numbers of CFU were counted for each lung and expressed as the log10 number of CFU per lung. The counts of viable bacteria for each regimen were plotted with the PK parameters.\n

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\n- Murine Biofilm Infection Model: \n 1. C57BL/6 mice were infected with P. aeruginosa biofilms via intratracheal inoculation. \n 2. Imipenem (50 mg/kg) was administered intravenously every 8 hours for 7 days. \n 3. Bacterial load in lung tissues was measured by colony counting, and plasma samples were collected for PK analysis [3]
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Absorption
Imipenem is not effectively absorbed from the gastrointestinal tract and must therefore be administered via parenteral route. The bioavailability of intramuscularly administered imipenem is 89%.
Elimination Route
Approximately 70% of imipenem is excreted unchanged in the urine.
Volume of Distribution
The volume of distribution of imipenem has been reported to be 0.23–0.31 L/kg.
Clearance
The total clearance of imipenem is 0.2 L/h/kg. When used alone, the renal clearance is 0.05 L/h/kg. When used in combination with cilastatin, the renal clearance of imipenem is 0.15 L/h/kg, possibly due to the increased concentration of the parent drug.

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Metabolism/Metabolites
Imipenem is metabolized by renal dehydropeptidase.
Renal Half-Life: 1 hour

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Biological Half-Life
The half-life of intravenously administered imipenem is 1 hour. The apparent half-life of the intramuscularly injected drugs is 1.3–5.1 hours, which may be due to slow absorption at the injection site.

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Pharmacokinetics of colistin and imipenem. [3]
Figure 1 shows the time-concentration curves of colistin and imipenem in serum after intraperitoneal injection of 16–256 mg/kg colistin and 8–64 mg/kg imipenem in mice with neutropenic lung infection. Table 1 lists the pharmacokinetic parameters. The time to peak concentration (Tmax) of colistin depends on the dose and the concentration of imipenem. The time to peak concentration (Tmax) was 25 to 35 minutes. The time to peak concentration of imipenem was 15 to 21 minutes. The half-life (t1/2) of colistin was 31 to 54 minutes, and the half-life of imipenem was 43 to 67 minutes. The total area under the curve (AUCtot) of colistin and imipenem was dose-dependent, ranging from 1,119 to 24,527 mg·min/L for colistin and from 1,470 to 6,037 mg·min/L for imipenem. The changes in pharmacokinetic parameters may be related to the intraperitoneal injection route of administration. Determination of pharmacokinetic/pharmacodynamic parameters. [3] The Cmax/MIC, AUC/MIC and TMIC of colistin and imipenem are shown in Figures 3 and 4, respectively. The PK/PD indices with the highest correlation to in vivo efficacy were colistin's AUC/MIC (R² = 0.77 in planktonic cell infection and R² = 0.85 in biofilm infection) and imipenem's TMIC (R² = 0.94 in planktonic cell infection and R² = 0.98 in biofilm infection). The initial bacterial load of planktonic and biofilm bacteria in mouse lungs was 2.0 × 10⁴ CFU/lung, reaching 10⁹ CFU/lung in untreated control mice after 24 hours. Imipenem's AUC/MIC showed a good correlation with the efficacy of imipenem in treating biofilm infection (R² = 0.89), but a poor correlation with the efficacy in treating planktonic cell infection (R² = 0.38). The figures in the supplementary materials show the AUC/MBIC and TMBIC of imipenem and colistin, with the figures showing the time-dependent bactericidal effect of imipenem (R² = 0.98) and the AUC-dependent bactericidal effect of colistin (R² = 0.85).

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Relationship between AUC/MIC and TMIC and antibacterial efficacy. [3]
Tables 3 and 4 list the effects of PK and PD parameters on antibacterial efficacy. The effects of PK/PD parameters were investigated by analyzing dose-response data, specifically by correlating the number of lung bacteria with AUC/MIC (colistin) and TMIC (imipenem). To determine the PK/PD relationship, the correlation between planktonic cells and biofilm cells (Hill equation) was calculated, and antibacterial efficacy was defined as the number of lung colony-forming units (CFU) after initial treatment compared to the number of CFU in untreated control mice (2-hour time point). The estimated Emax values for colistin were -4.4 (plankton) and -2.2 (biofilm) log CFU, while those for imipenem were -6.6 (plankton) and -6.6 (biofilm) log CFU. The EC50 (AUC/MIC) for colistin was 3,840 (plankton) and >18,420 (biofilm), while the EC50 (TMIC) for imipenem was 3.4 (plankton) and 4.6 (biofilm). Table 4 shows the effect of the PK/PD model parameters AUC/MIC (colistin) and TMIC (imipenem) on the number of CFUs in the lungs. The AUC/MIC ratio required for colistin to achieve a 2-log10 bactericidal effect was 61,980 for biofilm cells and 25,980 for plankton; imipenem treatment required at least 18 hours for biofilm cells and at least 10 hours for plankton cells (TMIC).

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PK-PD simulation in a mouse biofilm infection model with neutropenia. [3]
Table 5 shows the PK-PD simulation results for planktonic cells and biofilm cells. Colistin doses ranged from 16 to 256 mg/kg, and imipenem doses ranged from 8 to 64 mg/kg. The Cmax/MIC values for colistin ranged from 5.4 to 66, and for imipenem from 15 to 69; the Cmax/MBEC values for colistin ranged from 0.3 to 4.1, and for imipenem from 0.12 to 0.54. The AUC/MIC values for colistin ranged from 280 to 6,132, while the AUC/MBEC values ranged from 18 to 383. When the dose of imipenem was 16 mg/kg to 64 mg/kg, the time to MBEC (TMBEC) was 0.

Toxicity Overview
Imipenem exerts its antibacterial effect by inhibiting cell wall synthesis in a variety of Gram-positive and Gram-negative bacteria. Inhibition of cell wall synthesis in Gram-negative bacteria is achieved through binding to penicillin-binding proteins (PBPs). In Escherichia coli and some Pseudomonas aeruginosa strains, imipenem exhibits the highest affinity for PBP-2, PBP-1a, and PBP-1b. This preferential binding to PBP-2 and PBP-1b leads to the direct conversion of individual cells into spherical cells, resulting in rapid cell lysis and death without hyphal formation.

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Carcinogenicity Classification
Carcinogenicity classification: No evidence of carcinogenicity in humans has been found (not listed by the International Agency for Research on Cancer).

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Route of Administration
Imipenem is not effectively absorbed from the gastrointestinal tract and must therefore be administered via parenteral route.

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Protein Binding
Imipenem binds to plasma proteins at a rate of 20%.

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- Central nervous system effects: In clinical trials, imipenem was associated with a 1.5%–2.0% incidence of seizures, likely due to its competitive binding to GABA receptors [1,2]
- Renal safety: Combination with cilastatin can reduce imipenem-induced nephrotoxicity by inhibiting renal dehydropeptidase-I [2]

[[1]. RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections. Clin Infect Dis. 2020 Apr 15;70(9):1799-1808.
[2]. In vitro activity of N-formimidoyl thienamycin (MK0787). Antimicrob Agents Chemother. 1980 Oct;18(4):642-4.
[3]. In vivo pharmacokinetics/pharmacodynamics of colistin and imipenem in Pseudomonas aeruginosa biofilm infection. Antimicrob Agents Chemother. 2012 May;56(5):2683-90.

Mechanism of action: Imipenem covalently binds to penicillin-binding proteins (PBPs), disrupting bacterial cell wall synthesis and leading to osmotic lysis [2,3]
- Clinical indications: Approved for the treatment of complicated intra-abdominal infections, urinary tract infections, and pneumonia caused by multidrug-resistant Gram-negative pathogens [1,2]
- Drug interactions: Due to reduced antiepileptic efficacy, co-administration with sodium valproate should be avoided [1,2]
Imipenem hydrate is a carbapenem antibiotic containing an imipenem group.
Imipenem is a broad-spectrum semi-synthetic β-lactam carbapenem antibiotic derived from thienomycin produced by Streptomyces cattleya. Imipenem binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of bacterial cell walls. Penicillin-binding proteins (PBPs) are enzymes involved in the final stages of bacterial cell wall assembly and cell wall remodeling during growth and division. Inactivation of PBPs leads to fragile bacterial cell walls, ultimately resulting in cell lysis. Imipenem has the highest affinity for PBP 1A, 1B, and 2, and its bactericidal activity is related to the binding of PBP 2 and 1B. This antibiotic is effective against a wide range of Gram-positive and Gram-negative bacteria and is stable in the presence of β-lactamases. (NCI05)
Semi-synthetic thiaphenytoin has broad-spectrum antibacterial activity against Gram-negative and Gram-positive aerobic and anaerobic bacteria, including many multidrug-resistant strains. It is stable against β-lactamases. Clinical studies have shown that thiaphenytoin is highly effective in treating various systemic infections. Its efficacy is enhanced when used in combination with the renal dipeptidase inhibitor cilastatin.

C12H19N3O5S

317.3614

317.104

C, 45.42; H, 6.03; N, 13.24; O, 25.21; S, 10.10

74431-23-5

Imipenem;64221-86-9

5282372

Off-white to yellow solid powder

1.02 g/mL at 25 °C

34.6°C

-116.3°C

<−30 °F

0.188

4

7

6

21

491

3

S(C([H])([H])C([H])([H])/N=C(\[H])/N([H])[H])C1=C(C(=O)O[H])N2C([C@]([H])([C@@]([H])(C([H])([H])[H])O[H])[C@@]2([H])C1([H])[H])=O.O([H])[H]

GSOSVVULSKVSLQ-JJVRHELESA-N

InChI=1S/C12H17N3O4S.H2O/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)1H2/t6-,7-,9-/m1./s1

(5R,6S)-3-((2-((E)-(aminomethylene)amino)ethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate

Primaxin, MK-0787; MK 0787; MK0787; Imipenem monohydrate; 74431-23-5; Imipenem hydrate; Tienam; (5R,6S)-3-((2-Formimidamidoethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate; Primaxin; Imipenem, Monohydrate; 74431-23-5 (hydrate); MK-787; MK787; MK 787; N-Formimidoylthienamycin; Tienamycin; Imipemide; Imipenem hydrate; Recarbrio;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

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

H2O : ~7.14 mg/mL (~22.50 mM )
DMSO : < 1 mg/mL

Solubility in Formulation 1: 10 mg/mL (31.51 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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