Imipemide Other names: Imipenem

Imipenem, also referred to as N-formimidoyl-thienamycin, is a semi-synthetic derivative of thienamycin, the parent compound produced by the filamentous bacterium Streptomyces cattleya.

Imipenem exerts its bactericidal activity by inhibiting bacterial cell wall synthesis in Gram-positive and Gram-negative bacteria through binding to penicillin-binding proteins (PBPs).

Pharmacokinetic/Pharmacodynamic (PK/PD) relationship

Similar to other beta-lactam antibacterial agents, the time that imipenem concentrations exceed the MIC (T>MIC) has been shown to best correlate with efficacy.

Mechanism of resistance

Resistance to imipenem may be due to the following:

• Decreased permeability of the outer membrane of Gram-negative bacteria (due to diminished production of porins)
• Imipenem may be actively removed from the cell with an efflux pump.
• Reduced affinity of PBPs to imipenem
• Imipenem is stable to hydrolysis by most beta-lactamases, including penicillinases and cephalosporinases produced by gram-positive and gram-negative bacteria, with the exception of relatively rare carbapenem hydrolysing beta-lactamases. Species resistant to other carbapenems do generally express co-resistance to imipenem. There is no target-based cross-resistance between imipenem and agents of the quinolone, aminoglycoside, macrolide and tetracycline classes.

Breakpoints

EUCAST MIC breakpoints for imipenem to separate susceptible (S) pathogens from resistant (R) pathogens are as follows (v 1,1 2010-04-27):

• Enterobacteriaceae¹:__ S≤2 mg/l, R>8 mg/l

• Pseudomonas spp.²: S≤4 mg/l, R>8 mg/l
• Acinetobacter spp.: S≤2 mg/l, R>8 mg/l
• Staphylococcus spp.³: Inferred from cefoxitin susceptibility
• Enterococcus spp.: S≤4 mg/l, R>8 mg/l
• Streptococcus A, B, C, G: The beta-lactam susceptibility of beta-haemolytic streptococcus groups A, B, C and G is inferred from the penicillin susceptibility.
• Streptococcus pneumoniae⁴: S≤2 mg/l, R>2 mg/l
• Other streptococci⁴: S≤2 mg/l, R>2 mg/l
• Haemophilus influenzae⁴: S≤2 mg/l, R>2 mg/l
• Moraxalla catarrhalis⁴: S≤2 mg/l, R>2 mg/l
• Neisseria gonorrhoeae: There is insufficient evidence that Neisseria gonorrhoeae is a good target for therapy with imipenem.
• Gram-positive anaerobes: S≤2 mg/l, R>8 mg/l
• Gram-negative anaerobes: S≤2 mg/l, R>8 mg/l
• Non-species related breakpoints⁵: S≤2 mg/l, R>8 mg/l

¹ Proteus and Morganella species are considered poor targets for imipenem.
² The breakpoints for Pseudomonas relate to high dose frequent therapy (1g every 6 hours).
³ Susceptibility of staphylococci to carbapenems is inferred from the cefoxitin susceptibility.
⁴ Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
⁵ Non-species related breakpoint have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the overview of species-related breakpoints or footnotes.

Absorption

In normal volunteers, intravenous infusion of PRIMAXIN over 20 minutes resulted in peak plasma levels of imipenem ranging from 12 to 20 μg/ml for the 250 mg dose, from 21 to 58 μg/ml for the 500 mg dose, and from 41 to 83 μg/ml for the 1000 mg dose. The mean peak plasma levels of imipenem following the 250 mg, 500 mg, and 1000 mg doses were 17, 39, and 66 μg/ml, respectively. At these doses, plasma levels of imipenem decline to below 1 μg/ml or less in four to six hours.

Distribution

The binding of imipenem to human serum proteins is approximately 20%.

Biotransformation

When administered alone, imipenem is metabolised in the kidneys by dehydropeptidase-I. Individual urinary recoveries ranged from 5 to 40%, with an average recovery of 15-20% in several studies.

Elimination

The plasma half-life of imipenem was one hour. Approximately 70% of the administered antibiotic was recovered intact in the urine within ten hours, and no further urinary excretion of imipenem was detectable. Urine concentrations of imipenem exceeded 10 μg/ml for up to eight hours after a 500 mg dose. The remainder of the administered dose was recovered in the urine as antibacterially inactive metabolites, and faecal elimination of imipenem was essentially nil.

No accumulation of imipenem in plasma or urine has been observed administered as frequently as every six hours in patients with normal renal function.

Animal studies showed that the toxicity produced by imipenem was limited to the kidney.