Imipenem dosing

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." ... 

Adjust dose of imipenem/cilastatin based on body weight (refer to package insert). 

Isolated seizures that are not epilepsy can be caused by stroke, central nervous system trauma, central nervous system infections, metabolic disturbances (e.g., hyponatremia and hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures I or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsy-chotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants. 

Dual therapy with Cefepime, ceftazidime, imipenem, meropenem, Gentamicin or tobramycin 2 mg/kg loading dose... 

Monotherapy with imipenem 0.5 g IV every 6-8 hours, meropenem 1 g IV every 8 hours, ertapenem 1 g IV every 24 hours, extended-spectrum penicillins with a /3-lactamase inhibitor (piperacillin/tazobactam 4.5 g IV every 6 hours), or tigecycline 100 mg IV as loading dose, then 50 mg IV every 12 hours... 

Imipenem-Cilastatin IV Dosing Schedule for Adults with Normal Renal... 

IV IV infusion over 20 minutes results in peak plasma levels of imipenem antimicrobial activity that range from 14 to 83 mcg/mL, depending on the dose. Plasma levels declined to 1 mcg/mL or less in 4 to 6 hours. Peak plasma levels of cilastatin following a 20-minute IV infusion range from 15 to 88 mcg/mL, depending on the dose. The plasma half-life of each component is approximately 1 hour. Protein binding is 20% for imipenem and 40% for cilastatin. 

Imipenem urine levels remain above 10 mcg/mL for the 12-hour dosing interval following IM administration of 500 or 750 mg doses. Total urinary excretion of imipenem and cilastatin averages 50% and 75%, respectively, following either dose. 

Action Monobactam, -1- cell wall S5mth Dose Adul. 1—2 g IV/EM q6-12h Peds. Premature 30 mg/kg/dose IV ql2h Term children 30 mg/kg/dose q6-8h X in renal impair Caution [B, +] Disp Inj SE NA /D, rash, pain at inj site Interac tions T Effects W/probenecid, aminoglycosides, i-lactam antibiotics X effects W7 cefoxitin, chloramphenicol, imipenem EMS Monitor for S/Sxs of super Infxn may cause aUCTgic Rxns rare cross-sensitivity Rxns to penicillins and cephalosporins have been rqwrted OD May cause Szs symptomatic and supportive... 

Uses Serious Infxns d/t susceptible bacteria Action Bactericidal X cell wall synth Dose Adults. 250-1000 mg (imipenem) IV q6-8h, 500-750 mg IM 1/2 h Peds. 60-100 mg/kg/24 h IV q6h -1- if CrCl is <70 mL/min Caution [C, +/-] Probenecid T tox Contra Ped pts w/ CNS Infxn (t Sz risk) <30 kg w/ renal impair Disp Inj SE Szs if drug accumulates, GI upset, thromboc5rtopenia Interactions T Risks of Szs W/ cyclosporine, ganciclovir T effects W/ probenecid EMS Monitor for S/Sxs of sup Infxn T Sz risk w/ high doses monitor for signs of electrolyte disturbances and hypovolemia d/t D OD May cause N/V/D symptomatic and supportive... 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

Daily dosing is advantage over imipenem or meropenem Individualize treatment based on local susceptibility patterns. 

Carbapenems penetrate body tissues and fluids well, including the cerebrospinal fluid. All are cleared renally, and the dose must be reduced in patients with renal insufficiency. The usual dose of imipenem is 0.25-0.5 g given intravenously every 6-8 hours (half-life 1 hour). The usual adult dose of meropenem is 1 g intravenously every 8 hours. Ertapenem has the longest half-life (4 hours) and is administered as a once-daily dose of 1 g intravenously or intramuscularly. Intramuscular ertapenem is irritating, and for that reason the drug is formulated with 1% lidocaine for administration by this route. 

Answer B (Amoxicillin). The multiple extractions can lead to bacteremia while the mitral valve stenosis and cardiac insufficiency place him at risk for developing endocarditis. The present American Heart Association guidelines indicate amoxicillin (3 gm 1 hour prior to procedure and 1.5 gm 6 hours after original dose.) Vancomycin would only be appropriate if the patient was allergic to penicillins. Tetracycline and cotrimoxazole are bacteriostatic and not effective against the viridans group of Streptococci, the usual causative organism. Imipenem is also inappropriate since its spectrum is too broad. 

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). 

In animals, meropenem (17) and other carbapenems (18,19) were less epileptogenic than imipenem. In 403 children there was no meropenem-associated neurotoxicity (20) and meropenem was well tolerated in children with bacterial meningitis (21). In summary, a larger dose range of meropenem than imipenem appears to be tolerated, but when strictly observing known risk factors for seizure propensity the difference between the two compounds is very small (22,23). 

Drusano GL, Standiford HC, Bustamante Cl, Rivera G, Forrest A, Leslie J, Tatem B, Delaportas D, Schimpff SC. Safety and tolerability of multiple doses of imipenem/cilastatin. Clin Pharmacol Ther 1985 37(5) 539 3. 

A 20-year-old man with abdominal trauma received a single dose of piperacillin (1 g) followed by nine doses of imipenem + cilastatin (500 mg tds for 3 days) and 2 weeks later developed jaundice, fatigue, and pruritus (94). A liver biopsy showed centrilobular cholestasis, portal infiltration with eosinophils, and cholangitis. Lymphocyte transformation tests for piperacillin and imipenem/cilastatin were positive, suggesting an immunological mechanism. He made a full clinical and biochemical recovery after 3 months. 

In an earlier study of the effects of imipenem in the rabbit kidney it was shown that imipenem caused a significant decrease of mitochondrial respiration, deplehon of reduced glutathione, increased production of oxidized glutathione and lipid peroxidation [56]. However, these effects were less than those produced by a comparable nephrotoxic dose of cephaloridine [56]. Panipenem induced nephrotoxicity at a dose of 200 mg/kg, i.v., but this was less severe than that caused by a single dose of imipenem [57]. Simultaneous adminis-trahon of p-mipron (N-benzoyl-3-propionic acid) with imipenem and panipenem reduced the nephrotoxicity of these carbapenems by inhibiting the active transport of carbapenems in the renal cortex [57]. 

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 mi-... 

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. 

Pharmacokinetic studies have not been performed in horses however, i.v. doses of 0.7-1.Img/kg three times a day have been suggested as being suitable for use in small animals. Imipenem has to be administered i.v. because it is not absorbed following p.o. administration. Imipenem has been shown to penetrate inflamed meninges. It is metabolized extensively by the renal tubules to a potentially toxic compound. Therefore, it is usually combined with cilastatin, a drug that inhibits the renal tubular enzymes. The combined product produces high urine concentrations of active antibiotic and avoids renal toxicity. In the presence of cilastatin, 70% of a dose of imipenem is excreted unchanged in the urine. The half-life of imipenem in the dog is 30-45 nrin. 

Imipenem, a carbapenem antimicrobial, also possesses nephrotoxic potential. In animal models, nephrotoxicity is dose dependent and characterized by tubular necrosis. Interestingly, imipenem nephrotoxicity is markedly attenuated by co-administration of cilastatin, an inhibitor of the cytosolic and brush border enzyme dehydropeptidase I (DHP). Although DHP is responsible for hydrolyzing imipenem to inactive metabolites, the major protective effect of cilastatin appears to be due to inhibition of renal imipenem accumulation rather than DHP inhibition. 

Thienamycin (Fig. 10.5E) is a broad-spectrum p-lactam antibiotic with high P-lactamase resistance. Unfortunately, it is chemically unstable, although the N-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 10.5E) is stable to most P-lactamases but is readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropen-em, marketed more recently, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 10.5F. Ertapenem (Fig. 10.5G) has properties similar to those of meropenem but affords the additional advantage of once-daily dosing. 

To describe and evaluate dosing intervention program for imipenem OA Pre/post None ADRs, DCA Decreased number of seizure episodes cost savings due to dosage change Retrospective chart review... 

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. 

Newcomb, H.W. Hill, E.M. McCarthy, I.D. Mostow, S.R. Imipenem-cilastin dosing intervention program by pharmacists. Am. J. Hosp. Pharm. 1992, 49, 1133-1135. 

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