Reviews lmipenemjcilastatin: a very broad spectrum ~-lactam with a favourable side effect profile

lmipenem (N-formimidoyl thienamycin) is the first available semisynthetic amid1ne derivative of thienamycm, a 1j-lactam ant1b1otic produced by Streptomyces cattleya. lm1penem. in combmat1on with cilastatin, a renal dipeptidase mh1b1tor that mcreases unnary excret1on of active drug. represents the first commerc1ally ava1lable member of a new class of p-lactam ant1bacter1als - the carbapenems.

Most clinically important pathogens are susceptible lmipenem has been shown to. have an .

extremely wide spectrum of in v1tro ant1bactenal activity at a concentration of 8 mg/L 1m1penem inhibits more than 98% of clinically Important spec1es of pathogens. .

lmipenem is a potent inh1b1tor of most spec1es of Enterobacteriaceae. Aga1nst Pseudomonas aeruginosa. imipenem MIC90 values generally ranged between 2 and 8 mg/L and it was usually sim1lar 1n potency to ceftaz1d1me. lm1penem IS . extremely act1ve against Gram-negat1ve anaerobic bacteria in the ma1onty of m v1tro stud1es it was the most potent ant1bactenal evaluated aga1nst Bacteroides and Fusobacterium spec1es While im1penem mh1b1ts the maJority of strams of Haemophilus mfluenzae and Neisseria gonorrhoeae, 1nclud1ng penicliilnase-producmg stra1ns. 11 IS not as potent as some broad spectrum cephalosponns Against Legionella pneumophila in v1tro. 1mipenem was only slightly less potent than rifamp1c1n and erythromycm (based on MIC values) and it was the most potent bactericide. Chlamydia trachomatis and Flavobacterium group lib species are resistant to 1m1penem .

Most strains of staphylococci, streptococci and enterococci are susceptible to imipenem in vitro, although S faeCJum strains are highly resistant and some methiclilm-res1stant S aureus strams have been shown to have elevated MIC values, especially w1th prolonged incubation. Against Gram-pos1t1ve anaerobes imipenem is very potent: it was supenor to clmdamycm and comparable w1th metronidazole. Clin1cal ISOlates, except for a few strains of Clostndium dlfficile, were generally very susceptible

lm1penem demonstrates partial or full synergy when used in combination with a number of aminoglycos1des against various bacterial species, but in combination with other p-lactam drugs the interaction is normally antagonistic.

16 INPHARMA' 2 May 1987

lmipenem is not only very active against most p-lactamase producing species of bactena, 1t IS also an effective inhibitor of some p-lactamase enzymes. It is a potent inducer of p-lactamases elaborated by vanous bacterial spec1es. However. 1t remains a poor substrate for such enzymes and iis arJt,bacte;ial act;vity is maintained. The emergence of im1penem-res1stant stra1ns of P aerugmosa has been documented at a rate of 17 7% among over 400 1solates of th1s pathogen exposed to 1m1penemjcllastatm m therapeutic tnals. Emergence of res1stance 1n other bacterial species and cross-res1stance to other ant1bactenal drugs are both rare

Dose should be adjusted in impaired renal function Peak 1m1penem and C1lastat1n serum

concentrations of 30 to 35 mg/L are attained immediately after intravenous Infusion of imipenemjcilastatin 0.5g in healthy subjects. and imipenem concentrations are maintained above about 1 mgjl until 4 to 6 hours after infusion. Peak serum concentration and AUC appear to increase linearly with dose. Administration of cllastat1n with 1m1penem increases the AUC by 5 to 36% compared with administration of imipenem alone. Multiple-dose stud1es reveal no accumulation of the drugs m healthy adult subJects

Pharmacokinet1c data best fit a 2-compartment model. lm1penem IS up to 20% bound to human . plasma protein in vitro. Following usual therapeutiC doses of 1m1penemjcilastatm. concentrations of 1m1penem likely to be active against most susceptible organisms are achieved in a vanety of t1ssues and body flu1ds. mclud1ng sputum, lung, tonsil. maxillary s1nus. mastoid mucous membrane, k1dney. prostate tissue (but not fluid). bile, bile duct issue. female genital organs, intraperitoneal exudate. wound drainage fluid and cerebrospinal flu1d

Followmg the administration of imipenem; cilastatm 1n healthy subjects, 1mipenem and c1lastatm show s1milar elimination half-l1ves (about 1 hour). plasma clearances (0.18 to 0 22 L/hour; kg) and renal clearances (0.10 to 0.16 Lfhourjkg). lmipenem 1s part1ally metabolised to an open p-lactam ring der1vative by dehydropeptidase-1 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-1 and thus increases 6-hour urinary recovery of imipenem to 60-75% in all subjects when the drugs are administered as a 1 : 1 combination Almost all of radiolabelled doses of 1m1penem and cilastat1n are recovered in unne.

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Reduced glomerular filtrat1on rate increases the el1mination half-l1fe and decreases the renal clearance of im1penem and cllastatin Plasma concentrations of cilastatin are increased more than those of im1penem, which IS shunted into non-renal elimination pathways. Administration of 1mipenemjcilastatin 0.5g every 12 hours to haemod1alysis pat1ents between dialysis treatments leads to accumulation of cilastatin but not imipenem: trough cilastatin concentrations increase to as high as 100 mgjl Both drugs are removed from plasma by haemodialysis and a supplemental dose may be required after dialysis

The recommended adult dosage of 1mipenemj cilastatm is 0.25, 0.5 or 1 g administered Intravenously 6- to 8-hourly depending on the type and severiiy of 1nfeclio1·1. 111 moderate infection 1 g every 12 hours may be used Dosage should be reduced 1n patients w1th impa1rment of renal funct1on. beg1nn1ng at a creat1n1ne clearance of 70 mljmin/1 73m2 Patients with a creatinine clearance of less than 5 mljmln/1 73m2 should receive 1mipenemjcilastat1n only if on haemod1alysis.

Clinical efficacy rates are around 90% Cumulated results from phase II and Ill clinical

stud1es worldwide reveal imipenemjcilastatin 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 1nfect1ons IS 85% Total daily dosages of 1m1penemjcilastatin in these stud1es generally ranged from 1 to 4g

Equally encouraging are the cumulated bacterial erad1cat1on rates 92% for obstetric and gynaecological 1nfect1ons. 87% for intra-abdominal 1nfect1ons and 76% for lower respiratory tract 1nfect1ons. However. as reported with other .d-lactam antibactenals. colonisation and supennfect1on are not uncommon with imipenemj cllastat1n and occur at a sim1lar rate to that seen with these agents. Bactenal spec1es most frequently assoc1ated with colonisation or supennfection in imipenem-treated patients are Pseudomonas spec1es and Staphylococcus eptdermtdts. Indeed, isolation of imipenem-res1stant P aerugmosa from pat1ents Infected with 1m1penem-susceptible strams of this species prior to therapy occurs relat1vely frequently, pnmanly in patients with senous lower respiratory tract 1nfect1ons, many of whom are cured clinically; cross-res1stance to other antibacterial drugs IS rare.

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In randomised comparative trials, each of which 1ncluded infections of several body systems except the central nervous system, imipenemj cilastatin appeared to be similar in clinical efficacy to cefotaxime and ciprofloxac1n in moderate to severe infections and to cefazolin in mild to moderate infections. lmipenemjcilastatin clin1cally 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 imipenemjcilastatin 0.5g 6-hourly cured or improved 96% of 56 patients with serious infections vs 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 imipenemjcilastatin cured or improved 95% of 153 patients vs 87% of 158 patients treated with latamoxef 2g 8-hourly or 1 g 6- to 8-hourly.

In a third comparative study, the durations of hospitalisation and fever were significantly (p < 0.02) shorter with imipenemjcilastatin than gentam1c1njclindamycin. Three of these comparat1ve studies reported a lower incidence of laboratory abnormalities suggesting renal toxic1ty was less of a problem with imipenemjcilastat1n than with gentamicinjclindamycin.

Unfortunately, controlled comparative studies of imipenemjcilastatin in individual types of infection are few lmipenemjcilastatin 0.5g 6-hourly was not significantly different in clinical efficacy from gentam1cin (dosage adjusted according to serum concentrations) plus clindamycin 0.6g 6-hourly in 99 pat1ents with perforated and/or gangrenous append1cit1s, or in 24 patients w1th moderately severe abdommal Infections. However, both of these studies found that the durat1on of fever and hosp1tal1sat1on were S1gn1f1cantly (p < 0 05) shorter among the 1m1penemjc11astatm-treated pat1ents lmipenem/cllastatm 0 25g 3 t1mes dally cured or 1mproved 94% of 47 pat1ents w1th mira-abdominal 1nfect1ons vs 89% of 46 pat1ents cured w1th clindamyc1n 0.6g 6-hourly plus netllm1cln (dosage adjusted accord1ng to serum concentration): durat1on of hosp1tal1sal1on was also shorter among the im1penemjcllastat1n rec1p1ents. but stat1si1Cal analyses were not prov1ded for e1ther of these results. lm1penemjcilastatin 0 Sg 6-hourly appeared s1m1lar 1n clinical efficacy to latamoxef 2g 8-hourly 1n 45 patients with obstetric and gynaecolog1cal 1nfect1ons but no stat1st1cal analysis was prov1ded 98% of 42 patients adm1mstered 1m1penemj C1lastat1n 0.5g 6-hourly for 1nfect1ons of the skin were cured or 1mproved vs 84% of 50 patients admm1stered latamoxef 2g 8-hourly (p = 0.03).

INPHARIIIA~ 2 May 1987 17

Side effects are like those of other ~-lactams lmipenemjcliastatin is generally well tolerated

The most commonly reported side effects are similar to those of other {j-lactam antibactenals and include diarrhoea. nausea and vomiting. skin rashes, phlebitis at the InJection s1te. transient elevation of liver function test results and eos1nophil1a. Seizures have occurred in patients with CNS d1sorders. renal failure or other predisposing factors to seizure activity.

Potential applications are diverse lmipenemjcilastatin has a broader spectrum of

antimicrobial activity than that of any presently available cephalosporin or penicillin. As such, its most logical use is as empiric monotherapy of nosocomial infections 1n which aerobic Gram­negative bacilli, anaerobes and Gram-positive cocci may all be mvolved.

lmipenemjcilastatin is likely to be most valuable as a single agent in therapeutic situations which presently require the use of 2 or more potentially toxic antibacterials. This includes the treatment of intra-abdominal and pelvic infections involving mixed aerobic and anaerobic pathogens, in difficult-to-treat monomicrobial infections. and as empiric monotherapy of serious hospital-acquired infections such as septicaemia and respiratory tract infections. In these therapeutic situations, aerobic Gram-negative bacilli, anaerobes and S. aureus all might be implicated. In certain severe infections (particularly in respiratory tract infections), where P aeruginosa is a known component or there is a high likelihood of infection with this pathogen, the combined use of an aminoglycoside may prove valuable.lmportantly, unlike most {j-lactam antibiotics, imipenem/ cilastatin essentially lacks cross-resistance with other antibacterials including {1-lactam antibiotics: should resistance to imipenemjcilastatin develop 1n a strain of P aeruginosa, the efficacy of alternative antibacterials will not be compromised. Thus, the very broad spectrum of antibacterial and clinical activity of imipenemjcilastatin and its freedom from serious adverse effects offer 1mportant benefits. Clissold SP. Todd PA. Campoli R1chards DM Druqs 33 183·241 Mar

1987 j360 rcfercnccsJ

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