Cilastatin, with imipenem

Resistance As with other -lactam antibiotics, some strains of P. aeruginosa may develop resistance fairly rapidly during treatment with imipenem-cilastatin. Pseudomembranous colitis Pseudomembranous colitis has occurred with virtually all antibiotics. 

Drugs that may interact with imipenem-cilastatin include ganciclovir, probenecid, and cyclosporine. 

Edwards SJ, Emmas CE, Campbell HE. Systematic review comparing meropenem with imipenem plus cilastatin in the treatment of severe infections. Curr Med Res Opin. 2005 21 785-794. 

In humans, imipenem was foimd to be metabolized by an enzyme in the kidney, renal dehydropeptidase-I, which acts as a P-lactamase. Since the enzyme appears to serve no essential role in human metabolism, scientists were able to develop a synthetic competitive inhibitor, cilastatin, which they then used with imipenem to produce the combination drug, primaxin (Tienam). Primaxin was introduced into medical practice in 1985. 

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. 

Seizures associated with imipenem + cilastatin have repeatedly been reported (5-7). As with other beta-lac-tam antibiotics, it is difficult to assess clearly the cause of a seizure in patients with a cluster of other predisposing factors for neurotoxicity (8) and hence to reach clear estimates of frequency. In a review of 1754 patients there was a similar incidence of seizures with imipenem -I- cilastatin as with other antibiotic regimens usually containing another beta-lactam (9). In rabbits imipenem -I- cilastatin and another carbapenems were more neurotoxic than benzylpenicillin (10). In mice, ataxia and seizures were seen, with much lower blood concentrations of imipenem than cefotaxime or benzylpenicillin (1900 pg/ml versus 3400 qg/ml and 5800 qg/ml) (11). In mice imipenem also lowered the convulsive threshold of pentetrazol (pentylenetetrazole) more than cefazolin or two other carbapenems (12). Cilastatin alone was not proconvulsant, but it increased the effects of co-adminis-tered imipenem. 

Calandra GB, Brown KR, Grad LC, Ahonkhai VI, Wang C, Aziz MA. Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin. Am J Med 1985 78(6A) 73-8. 

Tse CS, Hernandez Vera F, Desai DV. Seiznre-Uke activity associated with imipenem-cilastatin. Drng Intell Clin Pharm 1987 21(7-8) 659-60. 

Calandra G, Lydick E, Carrigan J, Weiss L, Gness H. Factors predisposing to seiznres in serionsly ill infected patients receiving antibiotics experience with imipenem/ cilastatin. Am J Med 1988 84(5) 911-18. 

Donahue PE, Smith DL, Yellin AE, Mintz SI, Bur F, Luke DR. Trovafloxacin in the treatment of intra-abdominal infections results of a double-blind, multicenter comparison with imipenem/cilastatin. Trovafloxacin Surgical Group Am J Surg 1998 176(Suppl 6A) S53-61. 

Meropenem (Merrem IV) is a dimethylcarbamoyl pyro-lidinyl derivative of thienamycin. It does not require coadministration with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar to that of imipenem except that it may be less likely to cause seizures (0.5% of meropenem- and 1.5% of imipenem-treated patients seized). Its in vitro activity is similar to that of imipenem, with activity against some imipenem-resistant P. aeruginosa but less activity against Gram-positive cocci. Chnical experience with meropenem demonstrates therapeutic equivalence with imipenem. 

Sodium salt, CggH N NaOgS, cilastatin sodium. Off-white to yellowish-white hygroscopic, amorphous solid. pKa, 2.0 pKa2 4.4 pKa, 9.2. Very sol in water, methanol. Combination with imipenem Primaxin, Zienam. 

Imipenem, as well as thienamycin, penetrates very well through porins and is very stable, even inhibitory, to many (3-lactamases. Imipenem is not, however, orally active. When used to treat urinary tract infections, renal dehydropeptidase-1 hydrolyzes imipenem through hydrolysis of the (3-lactam and deactivates it. An inhibitor for this enzyme, cilastatin, is coadministered with imipenem to protect it. Inhibition of human dehydropeptidase does not seem to have deleterious consequences to the patient, making this combination highly efficacious against urinary tract infections. 

O Riordan J, Javed M, Doherty C, Hutchinson M. Worsening of myasthenia gravis on treatment with imipenem/cilastatin. JN irolNeurosurg Psychiatry (1994) 57, 383. 

Based on an early possible report, the manufacturer notes that generalised seizures have been reported in patients who received ganciclovir with imipenem-cilastatin. They recommend that ganciclovir and its prodrug valganciclovir should not be used with imipenem unless the benefits outweigh the risks.No further reports of this interaction appear to have been published, or reported to the manufacturer. Note that both ganciclovir and imipenem alone may cause seizures. 

Mraz W, Sido B, Knedel M, Hammer C. Concomitant immunosi5)pressive and antibiotic dier-apy-reduction of cyclosporine A blood levels due to treatment with imipenem/cilastatin. Transplant Proc (1987) 19,4017-20. 

Like other beta-lactam antibiotics, the carbapenems can cause seizures, which have been reported in association with imipenem + cilastatin 2, 3", 4, 5", 6, ], dori-penem /8, P 7, ertapenem [10, ll ], and panipenem [12 ]. 

In a review of 1754 patients there was a similar incidence of seizures with imipenem + cilastatin as with other antibiotic regimens usually containing another beta-lactam [3(f]. In another study, seven of 21 children developed seizure activity while receiving imipenem + cilastatin for bacterial meningitis [3T]. However, computer-assisted monitoring of imipenem + cilastatin dosages in relation to renal function resulted in a reduced incidence of seizures [32 ]. 

Karadeniz C, Oguz A, Canter B, Serdaroglu A. Incidence of seizures in pediatric cancer patients treated with imipenem/cilastatin. Pediatr Hematol Oncol 2000 17(7) 585-90. 

Fujishita M, Kataoka R, Eguchi T, Miyagi T, Kotani S, Takeuchi T, Taguchi H, Miyoshi I. Seizure and tremor occurring in acute leukemia patients treated with imipenem/cilastatin. Rinsho Ket-sueki 1989 30(3) 392-5. 

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

General Imipenem/cilastatin, meropenem, ertapenem, or extended-spectrum penicillins with 3-lactamase inhibitor 1. Aztreonam with clindamycin or metronidazole 2. Ciprofloxacin with metronidazole 3. Aminoglycoside with clindamycin or metronidazole ... 

Gangrenous or Imipenem/cilastatin, meropenem, ertapenem, 1. Aztreonam with clindamycin or metronidazole... 

Only patients with severe AP complicated by necrosis should receive infection prophylaxis with broad-spectrum antibiotics. Agents that cover the range of enteric aerobic gram-negative bacilli and anaerobic organisms should be started within the first 48 hours and continued for 2 to 3 weeks. Imipenem-cilastatin (500 mg every 8 hours) may be most effective a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) with metronidazole should be considered for penicillin-allergic patients. 

The first carbapenem released for clinical use was imipenem (5.46), a compound with relatively high resistance to microbial /3-lactamases. The addition of the (iminomethyl)amino side chain renders imipenem chemically more stable than thienamycin. But, like thienamycin, imipenem is also easily hydrolyzed by renal dehydropeptidase I, producing a mixture of /3-lactam ring-opened 1-pyrrolidine epimers at C(3) [161], The renal metabolism of imipenem can be minimized by co-administration of cilastatin (5.53), a competitive inhibitor of DHP-I [15 6] [162],... 

Imipenem undergoes enzymatic inactivation in the kidneys. In order to avoid this problem, it is used in a 1 1 ratio in combination with cilastatin—the sodium salt of [/ -[/ ,5 -(Z)]]-7-[(2-amino-2-carboxyethyl)thio]-2-[[(2,2-dimethylcyclopropyl)aminocarbonyl-2-heptenoic acid... 

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

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. 

---