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Imipenem/Cilastatin

An Update of its Antibacterial Activity, Pharmacokinetics and Therapeutic Efficacy in the Treatment of Serious Infections

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Abstract

Synopsis

The prototype carbapenem antibacterial agent imipenem has a very broad spectrum of antibacterial activity, encompassing most Gram-negative and Gram-positive aerobes and anaerobes, including most β-lactamase-producing species. It is coadministered with a renal dehydropeptidase inhibitor, cilastatin, in order to prevent its renal metabolism in clinical use.

Extensive clinical experience gained with imipenem/cilastatin has shown it to provide effective monotherapy for septicaemia, neutropenic fever, and intraabdominal, lower respiratory tract, genitourinary, gynaecological, skin and soft tissue, and bone and joint infections. In these indications, imipenem/cilastatin generally exhibits similar efficacy to broad-spectrum cephalosporins and other carbapenems and is at least equivalent to standard aminoglycoside-based and other combination regimens.

Imipenem/cilastatin is generally well tolerated by adults and children, with local injection site events, gastrointestinal disturbances and dermatological re-actions being the most common adverse events. Seizures have also been reported, occurring mostly in patients with impaired renal function or CNS pathology, or with excessive dosage.

Although it is no longer a unique compound, as newer carbapenems such as meropenem are becoming available, imipenem/cilastatin nevertheless remains an important agent with established efficacy as monotherapy for moderate to severe bacterial infections. Its particular niche is in treating infections known or suspected to be caused by multiresistant pathogens.

Antibacterial Activity

Imipenem is a parenteral carbapenem agent which is coadministered with cilastatin, a renal dehydropeptidase inhibitor, in order to prevent its renal metabolism. It is a compact molecule which penetrates well through the outer membrane of Gram-negative bacteria. Unlike many other β-lactam agents, imipenem has a postantibiotic effect against both Gram-positive and Gram-negative bacteria.

Imipenem has an excellent spectrum of in vitro activity which encompasses Enterobacteriaceae, including strains resistant to aminoglycosides and third generation cephalosporins (including ceftazidime), anaerobes and many Grampositive bacteria. Although imipenem has good activity against methicillin-susceptible Staphylococcus aureus and penicillin-susceptible Streptococcus pneumoniae, its activity is more variable against methicillin-resistant strains of S. aureus, penicillin-intermediate and -resistant strains of S. pneumoniae, coagulase-negative staphylococci and Enterococcus faecalis. Depending on the country, resistance rates among Pseudomonas aeruginosa to imipenem vary from 2.5 to 20%. Stenotrophomonas maltophilia is intrinsically resistant to imipenem. Comparative in vitro studies with newer carbapenem agents indicate that with the exception of meropenem, which has greater activity against Enterobacteriaceae, there is little to distinguish between imipenem and other agents. Imipenem showed synergy or partial synergy with amikacin against strains of P. aeruginosa resistant to imipenem and/or amikacin.

Alterations to outer membrane proteins leading to reduced permeability is the main mechanism of resistance to imipenem among Gram-negative bacteria. Imipenem is stable against hydrolysis by most chromosomal and plasmid-mediated β-lactamases, including extended-spectrum enzymes. β-Lactamases with carbapenemase activity are usually metalloenzymes. While these enzymes are common among certain species (S. maltophilia, Aeromonas spp. and Bacillus cereus), they remain rare among Enterobacteriaceae. Modification of the target site of imipenem (penicillin-binding proteins) is an important mechanism of resistance among Gram-positive bacteria.

Longitudinal epidemiological surveillance studies indicate that the sensitivity to imipenem among Enterobacteriaceae remains stable in most areas. Sensitivity of P. aeruginosa varies according to the country and hospital unit. Imipenem resistance among Bacteroides spp. is increasing in Japan, but apparently remains stable in other countries.

Pharmacokinetic Properties

Following administration of 0.5 and lg doses by intravenous infusion, peak plasma imipenem concentrations of 30 to 42 and 60 to 72 mg/L, respectively, are reached. Intramuscular administration produces lower peak concentrations (7.4 to 10.4 mg/L after a 0.5g dose).

Imipenem penetrates well into body tissues and fluids; concentrations >4 mg/L were measured in colonic, lung, pancreatic, peritoneal, prostatic or gynaecological tissue, bile, synovial, ascitic and skin window fluid, renal cortex and medulla following intravenous or intramuscular administration of imipenem/cilastatin 0.5 or lg. Lower concentrations were found in tonsillar tissue, sputum, prostatic fluid and CSF in the presence of inflamed meninges. The drug also crossed the placenta when administered to pregnant women and has been detected in breast milk in animals.

Imipenem has a relatively low volume of distribution at steady-state (14.4L) and protein binding of imipenem and cilastatin is low (<10 to 20% and 35%, respectively). Both compounds have relatively short elimination half-lives (approximately 1 hour in healthy individuals).

In patients with renal dysfunction, the elimination half-lives of imipenem and, particularly, cilastatin are prolonged in proportion to the degree of renal impair-ment, with values of 3 hours and 7 to 16 hours, respectively, in patients with end-stage renal failure. Thus, imipenem/cilastatin dosages must be adjusted ac-cording to renal function.

Therapeutic Efficacy

In clinical trials, imipenem/cilastatin was usually given intravenously, at a dosage of 0.5 to lg every 6 to 12 hours, but the intramuscular and intraperitoneal routes (the latter in patients undergoing continuous ambulatory peritoneal dialysis; CAPD) have also been used.

In the treatment of intra-abdominal infections, imipenem/cilastatin produced clinical cure in 69 to 97% of patients. Similar cure rates were achieved with imipenem/cilastatin in elderly patients with peritonitis and those with peritonitis associated with CAPD. In comparative studies, imipenem/cilastatin was generally at least as effective as standard aminoglycoside/antianaerobic combinations and was similar to meropenem monotherapy, but tended to be less effective than piperacillin/tazobactam. Imipenem/cilastatin was generally at least as effective as standard aminoglycoside-based, or other, combination regimens in patients with febrile neutropenia. It was also significantly more effective than ceftazidime monotherapy, cefuroxime plus tobramycin, cefalothin or cefuroxime plus gentamicin, or ceftazidime plus vancomycin, in this setting.

In the treatment of severe and/or nosocomial respiratory tract infections, imipenem/cilastatin achieved clinical cure or improvement in 67 to 90% of patients and was at least as effective as a combination of cefotaxime and amikacin (in infections not caused by P. aeruginosa) or ceftazidime monotherapy, but tended to be less effective than ciprofloxacin or pefloxacin monotherapy. As with other monotherapies, emergence of resistance and treatment failure were relatively common in patients with R aeruginosa infections treated with imipenem/cilastatin. In Japanese patients with less severe respiratory tract infections, imipenem/cilastatin exhibited similar efficacy to meropenem or panipenem/ betamipron.

Imipenem/cilastatin achieved clinical cure in approximately 80% or more of patients with septicaemia and showed similar efficacy to ceftazidime or a combination of cefotaxime and amikacin. Preliminary data from small numbers of patients suggest that imipenem/cilastatin is also effective in the treatment of endocarditis.

In the treatment of complicated urinary tract infections, mostly in Japanese patients, the clinical efficacy of imipenem/cilastatin was approximately 75 to 80% and was similar to that of meropenem and panipenem/betamipron. In patients with serious nosocomial urinary tract infections, imipenem/cilastatin 0.5g 6-hourly was as effective as ceftazidime 2g 12-hourly. Over 80% of patients with various obstetric or gynaecological infections were clinically cured or improved following treatment with imipenem/cilastatin, which was at least as effective as a combination of netilmicin and chloramphenicol.

Imipenem/cilastatin produced clinical cure or improvement in approximately 80% or more of patients with skin and soft tissue infections and was comparable to sulbactam/ampicillin in patients with limb-threatening diabetic foot infections. In the treatment of bone and joint infections, imipenem/cilastatin achieved clinical cure or improvement in 74 to 96% of patients.

Pharmacoeconomic Considerations

Although the acquisition cost of imipenem/cilastatin generally exceeds those of standard aminoglycoside combination regimens, this difference appears to be at least offset by the additional costs of multiple intravenous administration and monitoring (of plasma aminoglycoside concentrations and for renal and auditory toxicity) associated with the latter type of regimen. Pharmacoeconomic studies have shown a trend towards lower overall treatment costs for intra-abdominal infections with imipenem/cilastatin monotherapy compared with gentamicin plus clindamycin. Moreover, imipenem/cilastatin may reduce hospitalisation costs by shortening hospital stay. Although imipenem/cilastatin generally tended to be less effective than piperacillin/tazobactam in treating intra-abdominal infections, use of imipenem/cilastatin 0.5g 6-hourly in this setting was reported to result in a shorter hospital stay and lower hospitalisation costs than piperacillin/tazobactam 4g/0.5g 8-hourly.

In patients with neutropenic fever, imipenem/cilastatin was reported to be superior in terms of cost benefit, cost effectiveness and cost utility to a combination of amikacin and ceftazidime, although no actual costs were stated.

There are few published pharmacoeconomic data comparing imipenem/ cilastatin with other combination regimens or monotherapies such as broadspectrum cephalosporins and fluoroquinolones.

Tolerability

The most common clinical adverse events during treatment with imipenem/ cilastatin are local injection site events (2.7% of patients), gastrointestinal disturbances (nausea, vomiting, diarrhoea) and dermatological reactions. The most common laboratory adverse events are transient elevation of liver enzymes and eosinophilia. As with other β-lactam agents, imipenem/cilastatin has been reported to induce seizures: risk factors are excessive dosage, impaired renal function, head trauma or cerebrovascular accident and CNS pathology. Careful adjustment of imipenem/cilastatin dosage with regard to bodyweight and renal function is important, in order to minimise the risk of seizures.

Dosage and Administration

Imipenem/cilastatin is indicated for the treatment of septicaemia, neutropenic fever, endocarditis and intra-abdominal, lower respiratory tract, genitourinary, gynaecological, skin and soft tissue, and bone and joint infections. It is given by intravenous infusion over 20 to 30 minutes (doses ≤0.5g) or 40 to 60 minutes (larger doses), or a longer period if nausea develops. Alternatively, it may be administered by deep intramuscular injection, depending on the type of infection.

The recommended dosage of imipenem/cilastatin varies according to route of administration, type and severity of infection, pathogen susceptibility, renal function and bodyweight. The usual recommended intravenous adult dosage (based on bodyweight of 70kg) is 1 to 2 g/day in 3 to 4 daily doses, or a maximum of 50 mg/kg/day (not more than 4 g/day) in infections caused by less susceptible organisms. Dosage should be reduced in patients with lower bodyweight and/or impaired renal function. Dosage adjustment on the basis of advanced age is not necessary, although the age-related decline in renal function should be borne in mind. A dosage of 60 mg/kg/day, in 4 divided doses, is recommended for children aged ≥3 months and weighing <40kg, provided that total daily dose does not exceed 2g; those weighing ≥40kg may receive adult dosages. For surgical prophylaxis in adults, an intravenous dosage of lg at induction of anaesthesia and 3 hours later, followed by a further 0.5g at 8 and 16 hours in high-risk surgery, is recommended.

The intramuscular preparation is given at a dosage of 1 to 1.5 g/day, on a twice-daily basis, for treatment of mild to moderate infections. A single 0.5g dose may be used to treat gonococcal urethritis or cervicitis.

Imipenem/cilastatin is not recommended for the treatment of children aged <3 months or those with meningitis, and should be used with caution, with strict attention to correct dosage, in patients with CNS disorders and/or impaired renal function. If its use is deemed essential in a breastfeeding mother, breastfeeding should be discontinued. Because of apparent cross-reactivity between imipenem and other β-lactams, it should be ascertained whether previous hypersensitivity reactions have occurred with other β-lactams before initiating imipenem/ cilastatin therapy.

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    Julia A. Balfour, Harriet M. Bryson & Rex N. Brogden

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Various sections of the manuscript reviewed by: J.G. Bartlett, Division of Infectious Diseases, Department of Internal Medicine, Johns Hopkins University, Baltimore, Maryland, USA; M.P. Fink, Beth Israel Hospital, Boston, Massachusetts, USA; A. Freifeld, Pediatric Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; S. Geroulanos, Department of Surgery, Onassis Cardiac Surgery Center, Athens, Greece; H. Giamarellou, First Department of Propedeutic Medicine, Athens University School of Medicine, Laiko General Hospital, Athens, Greece; K. Hara, Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan; J. Kumazawa, Department of Urology, Faculty of Medicine, Kyushu University, Fukuoka, Japan; C.E. Nord, Department of Immunology, Microbiology and Infectious Diseases, Huddinge University Hospital, Karolinska Institutet, Huddinge, Sweden; J.S. Tan, Infectious Disease Service, Department of Medicine, Akron City Hospital, Akron, Ohio, USA; J. Turnidge, Microbiology Department and Infectious Diseases Unit, Monash Medical Centre, Clayton, Victoria, Australia; M.C. Vos, Department of Bacteriology, University Hospital Rotterdam, Rotterdam, The Netherlands.

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Balfour, J.A., Bryson, H.M. & Brogden, R.N. Imipenem/Cilastatin. Drugs 51, 99–136 (1996). https://doi.org/10.2165/00003495-199651010-00008

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