Imipenem renal function

Imipenem-cilastatin IV is not recommended in pediatric patients with CNS infections because of the risk of seizures and in pediatric patients less than 30 kg with impaired renal function, as no data are available. 

Renal function impairment Do not give imipenem-cilastatin IV to patients with Ccr less than or equal to 5 mL/min/1.73 m, unless hemodialysis is instituted within 48 hours. For patients on hemodialysis, imipenem-cilastatin IV is recommended only when the benefit outweighs the potential risk of seizures. 

Mechanism of Action A fixed-combination carbapenem. Imipenem penetrates the bacterial cell membrane and binds to penicillin-binding proteins, inhibiting cell wall synthesis. Cilastatin competitively inhibits the enzyme dehydropeptidase, preventing renal metabolism of imipenem. Therapeutic Effect Produces bacterial cell death. Pharmacokinetics Readily absorbed after IM administration. Protein binding 13%-21%. Widely distributed. Metabolized in the kidneys. Primarilyexcreted in urine. Removed by hemodialysis. Half-life 1 hr (increased in impaired renal function). 

The kidney plays a major role in the clearance of insulin from the systemic circulation, removing approximately 50% of endogenous insulin and a greater proportion of insulin administered to diabetic patients (19). Insulin is filtered at the glomerulus and reabsorbed by proximal tubule cells, where it is degraded by proteolytic enzymes. Insulin requirements are markedly reduced in diabetic patients with impaired renal function. Imipenem and perhaps other... 

Imipenem is used to treat septicaemia, particularly of renal origin, intra-abdominal infection and nosocomial pneumonia. In terms of imipenem, 1-2 g/d is given by i.v. infusion in 3-4 doses reduced doses are recommended when renal function is impaired. 

Imipenem is a more common cause of seizures than other beta-lactam antibiotics, particularly when high doses are given (13-15). In one study, seven of 21 children developed seizure activity while receiving imipenem + cilastatin for bacterial meningitis, a recognized risk factor (13). However, computer-assisted monitoring of imipenem + cilastatin dosages in relation to renal function resulted in a reduced incidence of seizures (16). 

Most common side effects include diarrhea, nausea, vomiting, headache, rash, and infusion-related reactions. Frequency and potential risk of seizures with imipenem appear to be greater in comparison with the other carbapenems and beta-lactam antibiotics. Seizures have occurred most commonly in patients with CNS disorders or bacterial meningitis and/or compromised renal function. May be prevented by dose adjusting for renal insufficency. Pseudomembranous colitis. 

UACH To evaluate impact of renal function monitoring program, focusing on appropriate dosages of imipenem OD None None DCA Potential to save 11,500 annually by adjusting imipenem dosages on basis of renal function Input costs not considered no control group clinical outcomes not considered... 

Ritchie, D.J. Reichley, R.M. Canaday, K.L. Bailey, T.C. Evaluation and financial impact of imipenem/cilastatin dosing in elderly patients based on renal function and body weight. J. Pharm. Technol. 1993, 9, 160-163. 

Drug therapy individualization for the patient receiving CRRT is complicated by the fact that patients with ARF may have a higher residual nonrenal clearance of some drugs than patients with CKD who have a similar CLcr. " " For example, the nonrenal clearance of imipenem in patients with ARF (91 mL/min) is between the values observed in CKD patients (50 mL/min) and those with normal renal function (130 mL/min)." This may occur because of less exposure to or accumulation of uremic by-products thatmay alter hepatic function. A nonrenal clearance value in a patient with ARF that is higher than anticipated based on chronic renal failure data would result in lower than expected, possibly subtherapeutic, serum concentrations. For example, in order to maintain comparable serum concentration, the imipenem dose requirement in patients with ARF would be 2,000 mg/ 24 hours as compared to the recommended dosage for patients with ESKD of 1,000 mg/24 hours." ... 

It is incumbent on health professionals to avoid toxic drugs whenever possible. Antibiotics associated with CNS toxicities, usually when not dose-adjusted for renal function, include penicillins, cephalosporins, quinolones, and imipenem. Hematologic toxicities generally are manifested with prolonged use of nafcillin (neutropenia), piperacillin (platelet dysfunction), cefotetan (hypoprothrombinemia), chloramphenicol (bone marrow suppression, both idiosyncratic and dose-related toxicity), and trimethoprim (megaloblastic anemia). Reversible nephrotoxicity classically is associated with aminoglycosides... 

Several transplant patients with impaired renal function have experienced adverse CNS effects (including convulsions and tremors) while taking imipenem/cilastatin and ciclosporin. Imipenem/cilastatin may affect ciclosporin levels. 

It should be noted that focal tremors, myoclonus and convulsions are a known adverse effects of imipenem/cilastatin and are most likely to occur in patients with reduced renal function. However, the patients cited above received imipenem/cilastatin in doses adjusted for their renal function. The manufacturers of imipenem/cilastatin recommend that patients who develop focal tremors, myoclonus and convulsions while receiving the antibacterial should be started on an antiepileptic drug. If symptoms persist the dose should be reduced, or the drug withdrawn. ... 

The safety profile of the carbapenems is comparable to that of other beta-lactam antibiotics, in particular with regard to laboratory abnormalities, the most common ones being those related to liver function (3,4). In patients with pre-existing nervous system disease or who take dosages above the recommended limits (for example in renal impairment) seizures appear to be more common with imipenem + cilastatin. 

It has been suggested that mitochondrial injury may mediate, at least in part, the nephrotoxicity of some P-lactams [67]. Mitochondrial respiration with and uptake of succinate after exposure to toxic doses of cephaloridine, cephaloglycin, or imipenem [98] showed significant reduction of both functions. Cephalexin did not affect either the mitochondrial uptake or respiration with succinate. Depressed mitochondrial respiration secondary to acylation of the mitochondrial transporter for succinate appears to be implicated in renal toxicity caused by cephalosporins and carbapenems [98]. The organic anion fluorescein accumulates in mi-... 

Susceptibility fiictois The proconvulsant activity of the carbapenems, particularly imipenem, has limited their usefulness in patients at high risk of seizures, such as patients with nervous system infections, especially meningitis, chronic or acute nervous system damage, and more generally in patients with compromised rerud function and a reduced threshold for seizure activity. The risk of seizures due to carbapenems is increased by renal insufficiency... 

In 1985, the self-inactivating property of thienamycin was overcome by the use of a terminal imino functionality which is less nudeophilic. Imipenem (Fig. 22.32) has a broad spectrum of activity and is administered by deep intramuscular injection or as an intravenous infusion. Renal dehydropeptidase 1, an enzyme present in the kidney, attacks and inactivates imipenem. This problem has been overcome by the co-administration of imipenem with cilastatin, a renal dehydropeptidase 1 inhibitor. Mer-openem (Fig. 22.32), an analogue introduced in 1996, is stable to the action of renal dehydropeptidase 1 and is also administered by deep intramuscular injection or as an intravenous infusion. Since the discovery of thienamycin in 1976, only parenteral analogues have heen successfully used clinically because the carhapenem structure is unstable in both the stomach and intestine. 

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