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Imipenem/Cilastatin

A Review of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Efficacy

Summary

Synopsis

Imipenem is the first available semisynthetic thienamycin and is administered intravenously in combination with cilastatin,1 a renal dipeptidase inhibitor that increases urinary excretion of active drug. In vitro studies have demonstrated that imipenem has an extremely wide spectrum of antibacterial activity against Gram-negative and Gram-positive aerobic and anaerobic bacteria, even against many multiresistant strains of bacteria. It is very potent against species which elaborate β-lactamases.

Imipenem in combination with equal doses of cilastatin 2 has been shown to be generally well tolerated and an effective antimicrobial for the treatment of infections of various body systems. It is likely to be most valuable as empirical treatment of mixed aerobic and anaerobic infections, bacteraemia in non-neutropenic patients and serious hospital-acquired infections.

Antibacterial Activity

Imipenem is an amidine derivative of thienamycin which has been shown to have an extremely wide spectrum of in vitro antibacterial activity, including most aerobic and anaerobic Gram-negative and Gram-positive bacteria. Indeed, at a concentration of 8 mg/L imipenem inhibits greater than 98% of clinically important species of pathogens.

Imipenem is a potent inhibitor of most species of Enterobacteriaceae (more than 95% of clinical isolates being inhibited at a concentration of 2 mg/L), even of strains exhibiting resistance to a number of antimicrobial drugs. Against Pseudomonas aeruginosa, imipenem MIC90 values generally ranged between 2 and 8 mg/L, even against some multi-resistant strains, and it was usually similar in potency to ceftazidime. P. maltophilia and many strains of P. cepacia are resistant to the effects of imipenem. Imipenem is extremely active against Gram-negative anaerobic bacteria; in the majority of in vitro studies it was the most potent antibacterial evaluated against Bacteroides and Fusobacterium species. While imipenem inhibits the majority of strains of Haemophilus influenzae and Neisseria gonorrhoeae, including penicillinase-producing strains, it is not as potent as some broad spectrum cephalosporins. Against Legionella pneumophila in vitro, imipenem was only slightly less potent than rifampicin and erythromycin (based on MIC values), and it was the most potent bactericide. Chlamydia trachomatis and Flavobacterium group IIb species are resistant to imipenem.

Most strains of staphylococci, streptococci and enterococci are susceptible to imipenem in vitro, although S. faecium strains are highly resistant and some methicillin-resistant S. aureus strains have been shown to have elevated MIC values, especially with prolonged incubation. Against Gram-positive anaerobes imipenem is very potent; it was superior to clindamycin and comparable with metronidazole. Clinical isolates, except for a few strains of Clostridium difficile, were generally very susceptible.

Imipenem is a bactericidal antimicrobial which has a strong affinity for the penicillin-binding proteins (especially PBP 2) in bacterial species investigated — usually resulting in rapid cell swelling and lysis. Generally, the MIC of imipenem for most strains is little affected by increases in inoculum size (up to 106 colony-forming units/ml), by different media (apart from thioglycolate and high-cysteine containing broths), by pH (between 5.5 and 8.5), or by the addition of horse serum (10 to 50%). Imipenem demonstrates partial or full synergy when used in combination with a number of aminoglycosides against various bacterial species, but in combination with other β-lactam drugs the interaction is normally antagonistic.

Imipenem is not only very active against most β-lactamase producing species of bacteria, it is also an effective inhibitor of some β-lactamase enzymes. It is a potent inducer of β-lactamases elaborated by various bacterial species. However, it remains a poor substrate for such enzymes and its antibacterial activity is maintained. The emergence of imipenem-resistant strains of P. aeruginosa have been documented at a rate of 17.7% among over 400 isolates of this pathogen exposed to imipenem/cilastatin in therapeutic trials. Resistance developed mainly in severely ill patients with lower respiratory tract infections, many of whom were clinically cured by the antibacterial regimen. Emergence of resistance in other bacterial species and cross-resistance to other antibacterial drugs are both rare.

Cilastatin, which is coadministered with imipenem to improve the urinary recovery of active drug, is devoid of antibacterial activity and inhibitory effects on β-lactamases, and neither potentiates nor antagonises the effects of imipenem.

Pharmacokinetics

Peak imipenem and cilastatin serum concentrations of 30 to 35 mg/L are attained immediately after intravenous infusion of imipenem/cilastatin 0.5g in healthy subjects, and imipenem concentrations are maintained above about 1 mg/L until 4 to 6 hours after infusion. Peak serum concentration and area under the concentration-time curve (AUC) appear to increase linearly with dose. Administration of cilastatin with imipenem increases the AUC by 5 to 36% compared with administration of imipenem alone. Multiple-dose studies reveal no accumulation of the drugs in healthy adult subjects.

Pharmacokinetic data best fit a 2-compartment model. The mean total apparent volumes of distribution reported for imipenem and cilastatin range from 16.3 to 29.5L and 14.6 to 20.1L, respectively, and corresponding values for the central compartment are 9.4 to 12.9L and 8.8 to 19.1L. Imipenem is up to 20% bound to human plasma protein in vitro. Following usual therapeutic dosages of imipenem/cilastatin, concentrations of imipenem likely to be active against most susceptible organisms are achieved in a variety of tissues and body fluids, including sputum, lung, tonsil, maxillary sinus, mastoid mucous membrane, kidney, prostate tissue (but not fluid), bile, bile duct tissue, female genital organs, intraperitoneal exudate, wound drainage fluid and cerebrospinal fluid. Rapid placental transfer of imipenem and cilastatin occurs, and while transfer into breast milk has not been studied in humans, it occurs in rats.

Following the administration of imipenem/cilastatin in healthy subjects, imipenem and cilastatin show similar elimination half-lives (about 1 hour), plasma clearances (0.18 to 0.22 L/h/kg) and renal clearances (0.10 to 0.16 L/h/kg). The renal clearance of imipenem is reduced to 0.04 to 0.06 L/h/kg when administered alone. Imipenem is partially metabolised to an open β-lactam ring derivative by dehydropeptidase-I in the proximal renal tubule, and 6-hour urinary recovery of active imipenem varies from 7 to 45% in individual subjects when given alone. Cilastatin inhibits dehydropeptidase-I and thus increases 6-hour urinary recovery of imipenem to 60 to 75% in all subjects when the drugs are administered as a 1: 1 combination. Almost all of radiolabelled doses of imipenem and cilastatin are recovered in urine. Most cilastatin is recovered unchanged (about 80%) and some (12%) as N-acetyl cilastatin.

In neonates, trough cilastatin plasma concentrations are about 10 times those of imipenem but no accumulation occurs with repeated doses of imipenem/cilastatin 10 mg/kg/day every 12 hours. Reduced glomerular filtration rate increases the elimination half-life and decreases the renal clearance of imipenem and cilastatin. Plasma concentrations of cilastatin are increased more than those of imipenem, which is shunted into non-renal elimination pathways. Administration of imipenem/cilastatin 0.5g every 12 hours to haemodialysis patients between dialysis treatments leads to accumulation of cilastatin but not imipenem; trough cilastatin concentrations increase to as high as 100 mg/L. Both drugs are removed from plasma by haemodialysis and a supplemental dose may be required after dialysis.

Therapeutic Trials

Cumulated results from phase II and III clinical studies worldwide reveal imipenem/cilastatin clinical efficacy rates of at least 95% for bacteraemia, urinary tract infections and obstetric and gynaecological infections. Clinical efficacy rates are greater than 90% for soft tissue, bone and joint, and intra-abdominal infections, and the clinical efficacy rate for lower respiratory tract infections is 85%. Total daily dosages of imipenem/cilastatin in these studies generally ranged from 1 to 4g.

Equally encouraging are the cumulated bacterial eradication rates: 92% for obstetric and gynaecological infections, 87% for intra-abdominal infections and 76% for lower respiratory tract infections. However, as reported with other β-lactam antibacterials, colonisation and superinfection are not uncommon with imipenem/cilastatin and occur at a similar rate to these agents. Bacterial species most frequently associated with colonisation or superinfection in imipenem-treated patients are Pseudomonas species and Staphylococcus epidermidis. Indeed, isolation of imipenem-resistant P. aeruginosa from patients infected with imipenem-susceptible strains of this species prior to therapy occurs relatively frequently, primarily in patients with serious lower respiratory tract infections, many of whom are cured clinically; cross-resistance to other antibacterial drugs is rare.

In randomised comparative trials, each of which included infections of several body systems except the central nervous system, imipenem/cilastatin appeared to be similar in clinical efficacy to cefotaxime and ciprofloxacin in moderate to severe infections and to cefazolin in mild to moderate infections. Imipenem/cilastatin clinically cured or improved a greater percentage of patients than did gentamicin plus clindamicin in 4 comparative studies and a greater percentage of patients than did latamoxef (moxalactam) in 3 comparative studies; 4 of these studies analysed the results statistically, and 2 found statistically significant differences in clinical efficacy between treatments. In the first of these 2 studies imipenem/cilastatin 0.5g 6-hourly cured or improved 96% of 56 patients with serious infections versus 84% of 62 patients treated with gentamicin (dose adjusted according to serum concentrations) plus clindamycin 0.6g 6-hourly (p < 0.05); bacterial eradication rates did not differ significantly. In the second study the same dosage of imipenem/cilastatin cured or improved 95% of 153 patients versus 87% of 158 patients treated with latamoxef 2g 8-hourly or 1g 6- to 8-hourly.

In a third comparative study, the durations of hospitalisation and fever were significantly (p < 0.02) shorter with imipenem/cilastatin than gentamicin/clindamycin. Three of these comparative studies reported a lower incidence of laboratory abnormalities suggesting renal toxicity was less of a problem with imipenem/cilastatin than with gentamicin/clindamycin.

Unfortunately, controlled comparative studies of imipenem/cilastatin in individual types of infection are few. Imipenem/cilastatin 0.5g 6-hourly was not significantly different in clinical efficacy from gentamicin (dosage adjusted according to serum concentrations) plus clindamycin 0.6g 6-hourly in 99 patients with perforated and/or gangrenous appendicitis, or in 24 patients with moderately severe abdominal infections. However, both of these studies found that the duration of fever and hospitalisation were significantly (p < 0.05) shorter among the imipenem/cilastatin-treated patients. Imipenem/cilastatin 0.25g 3 times daily cured or improved 94% of 47 patients with intra-abdominal infections versus 89% of 46 patients cured with clindamycin 0.6g 6-hourly plus netilmicin (dosage adjusted according to serum concentration); duration of hospitalisation was also shorter among the imipenem/cilastatin patients, but statistical analyses were not provided for either of these results. Imipenem/cilastatin 0.5g 6-hourly appeared similar in clinical efficacy to latamoxef 2g 8-hourly in 45 patients with obstetric and gynaecological infections but no statistical analysis was provided. 98% of 42 patients administered imipenem/cilastatin 0.5g 6-hourly for infections of the skin were cured or improved versus 84% of 50 patients administered latamoxef 2g 8-hourly (p = 0.03).

Side Effects

Imipenem/cilastatin is generally well tolerated. The most commonly reported side effects are similar to those of other β-lactam antibacterials and include diarrhoea, nausea and vomiting, skin rashes, phlebitis at the injection site, transient elevation of liver function test results and eosinophilia. Seizures have occurred in patients with CNS disorders, renal failure or other predisposing factors to seizure activity.

Dosage and Administration

The recommended adult dosage of imipenem/cilastatin is 0.25, 0.5 or 1g administered intravenously 6- to 8-hourly depending on the type and severity of infection: in moderate infection 1g every 12 hours may be used. Dosage should be reduced in patients with impairment of renal function, beginning at a creatinine clearance of 70 ml/min/1.73m2. Patients with a creatinine clearance of less than 5 ml/min/1.73m2 should receive imipenem/cilastatin only if on haemodialysis.

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Correspondence to Stephen P. Clissold.

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Various sections of the manuscript reviewed by: J.F. Acar, Service De Microbiologie Medicale, Hôpital Saint-Joseph, Paris, France; V.P. Ackerman, Department of Microbiology, Royal North Shore Hospital, St Leonards, Australia; C.J. Fernandes, Department of Microbiology, Royal North Shore Hospital, St Leonards, Australia; A.M. Geddes, Department of Medicine, The University of Birmingham, Birmingham, England; R.N. Jones, Laboratories of the Kaiser-Permanente Medical Care Program, Clackamas, Oregon, USA; Y. Kawada, Department of Urology, Fukui Medical School, Fukui-Ken, Japan; T. Kesado, Institute of Anaerobic Bacteriology, Gifu University School of Medicine, Gifu, Japan; H.C. Neu, Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York, USA; C.E. Nord, Department of Microbiology, Karolinska Institutet, Huddinge, Sweden; S.R. Norrby, Department of Infectious Diseases, University of Umeå, Umeå, Sweden; A.D. Russell, Welsh School of Pharmacy, University of Wales Institute of Science and Technology, Cardiff, Wales; A. Saito, Nagasaki University School of Medicine, Second Department of Internal Medicine, Nagasaki, Japan; D.J. Winston, Division of Infectious Diseases, Department of Medicine, UCLA Center for the Health Sciences, Los Angeles, California, USA; R. Wise, Department of Medical Microbiology, Dudley Road Hospital, Birmingham, England.

Imipenem plus cilastatin: ‘Primaxin’, ‘Tienam’, ‘Zienam’ (Merck Sharp and Dohme).

Unless otherwise stated, only the dose of imipenem is quoted in this review with the understanding that an equal amount of cilastatin was also administered.

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Clissold, S.P., Todd, P.A. & Campoli-Richards, D.M. Imipenem/Cilastatin. Drugs 33, 183–241 (1987). https://doi.org/10.2165/00003495-198733030-00001

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Keywords

  • Antimicrobial Agent
  • Cefotaxime
  • Imipenem
  • Cefoperazone
  • Antimicrobial Chemotherapy